Novel benzamidine derivatives, process for the preparation thereof and pharmaceutical composition comprising the same

ABSTRACT

The present invention relates to novel benzamidine derivatives, process for the preparation thereof and pharmaceutical composition comprising the same. The novel benzamidine derivatives of the present invention are useful for the prevention and treatment of osteoporosis, bone fractures and allergic inflammatory diseases.

TECHNICAL FIELD

The present invention relates to novel benzamidine derivatives, processfor the preparation thereof and pharmaceutical composition comprisingthe same.

BACKGROUND ART

Bone is the body's framework. Bone contains calcium (Ca²⁺) and plays animportant role in maintaining the calcium level in blood. To this end,the growth of bone is a metabolic balance between the activity ofosteoblasts and osteoclasts in the bone remodeling cycle.

When the balance between bone absorption and bone formation isdisrupted, the amount of bone tissue replaced by osteoblasts fails tomatch that absorbed by osteoclasts, thus leading to osteoporosis, acommon condition which result in the loss of bone density or bone mass.This disease frequently occurs in middle-aged or elderly women.

Osteoporosis is a metabolic bone disease, which results from adisturbance in the normal bone remodeling, tilting the balance betweenbone resorption and formation, thus resulting in bone loss and fracturesafter mineral flux. Bone is the dynamic structures, in which theosteoblast bone formation and osteoclast bone resorption arecontinuously occurred.

Previous studies focused on the metabolisms of bone inorganic materialslike calcium and inorganic phosphorus. Such studies did not providesufficient findings regarding the mechanisms of osteoporosis.

Although bisphosphonates (alendronate, etidronate etc.), hormones(raloxifen), Vitamin D, Calcitonin, calcium agents, etc. have been usedas anti-osteoporetic agents, they have some adverse side effect ordefects. Bisphosphontes show low pharmacokinetic profiles, are difficultto dose and may induce esophagitis. Hormone agents must be administeredcontinuously. Also, in case of long term therapy, severe side effectssuch as breast cancer, gallstones and embolism may be induced. Vitamin Dagents are expensive and show little efficacy in treatingestrogen-deficient osteoporetic patients. Calcitonin is also veryexpensive and difficult to administrate. Calcium has few adverse sideeffects, but its effects is restricted to the prevention of osteoporosisnot the treatment of it.

Osteoporosis requires long term therapy, thus it is necessary for thedevelopment of new drugs to not include the above-mentioned adverseeffects.

A bone fracture is a break or crack in a bone, with complete orincomplete disruption of the continuity of a bone, epiphyseal plate orarticular surface. A bone fracture is caused mostly by some type oftrauma to a bone. This trauma might occur as a result of a motor vehicleaccident, workplace accident, physical abuse, repetitive stress such asexercise, heavy lifting, etc. According to fracture line (line alongepiphyseal ends generated upon fracture), bone fractures are classifiedinto fissured fractures, greenstick fractures, transverse fractures,oblique fractures, spiral fractures, segmental fractures, comminutedfractures, avulsion fractures, compression fractures, depressedfractures, etc.

It is common for bone fractures to injure blood, thus resulting inpartial hemorrhage and blood clots. In addition, the bone matrix arounda fracture region breaks down or ruptures, with the death of osteocytes.During a fracture healing process, hence, the blood clots and theinjured osteocytes and bone matrix are removed by macrophages whileosteoprogenitor cells of the perilsteum and endosteum around thefracture region actively proliferate to form cellular tissue around thefracture region and are then integrated with the fracture region. In theconnective tissue of the fracture region, either a bone tissue arises byendochondral ossification from a small cartilage fragment or an immaturebone is formed by intramembranous ossification. Accordingly,intramembranous ossification from mesenchymal tissue and endochondralossification are observed concurrently in the connective tissue of afracture region. The trabecula of the immature bone irregularly formedin this way temporarily connects ends of the fractured bone fragments,resulting in the formation of a bony callus. The woven bone of the bonycallus formed in the fracture region is gradually resorbed as thehealing process progresses, and undergoes rearrangement resulting in thedevelopment of lamellar bone.

The healing process for fracture is largely divided into three phases:inflammatory phase, bone reparative phase, and remodeling phase.

In the inflammatory phase, inflammatory responses occur since tissuesaround a fracture region are injured and hematoma fills the fracturegap.

In the bone reparative phase, the hematoma is removed from the fracturegap and substituted with granulation tissue while soft callus is formed.According to the osteogenesis mechanism, two processes proceedconcurrently: endochondral ossification, in which the soft callus isremodeled into hard callus, and fibrous/intramembranous ossification, inwhich a new bone is formed by osteogenic cells.

In the remodeling phase, newly formed bone tissue is extended over along period of time by the orchestrated action of osteoclastic boneresorption and osteoblastic bone formation, with the correction of bonedistortions and the reinforcement of bone defects.

During the remodeling phase, patients with a bone fracture conduct theirlives without great difficulty because the newly formed bone has becomehard to some extent, but the nascent bone tissue in the reparative phaseis not hard enough for patients to live their daily lives withoutdifficulty. In addition, the reparative phase is long. Thus, it isclinically important for a fracture curative to have the function ofshortening the reparative phase as well as regenerating a fractured boneinto a complete bone by promoting the complex fracture healing process.

There are various promoters for fracture healing. Peptides havingphysiologically active functions, such as bone morphogenic proteins(BMPs) and transforming growth factors (TGFs), are found to be involvedin the fracture healing process (Proc. Natl. Acad. Sci., USA, vol. 87,pp. 2220-2224 (1989)). Also, it has been studied that an increase inintracellular cyclic AMP level by use of a phosphodiesterase (PDE)inhibitor can lead to an increase in bone mass. For example, it isreported that mice, into which the general PDE inhibitor pentoxipyllineor the selective PDE4 inhibitor rolipram had been subcutaneouslyinjected every day, were observed to have the vertebrate and femurincreased in bone mineral density, and showed hyperplasia of corticalbones (Bone, vol. 27, 6th edition, pp. 811-817 (2000)).

As mentioned above, attention has long been paid to osteogenesis andfracture healing, and extensive studies on fracture healing processeshave been conducted from various points of view, including geneticfactors, adolescent influence, hematopoietic effect, fixture effect,bone grafts, other healing promoting factors, etc. (Kawamura, M andUrist M R., Clin. Orthop., 236, 240-248, 1988).

Fracture healing requires a significant period of time and elderlypatients with osteoporosis tend to suffer more from bone fractures.Falling short of the expectation of usefulness in fracture healing,currently available therapeutic agents for the treatment ofosteoporosis, such as calcium, estrogen, calcitonin, active vitamin D,biphosphonate, etc., are found only to lower the risk of fracture byobstructing the decrease of bone density, and have no function ofjoining fractured bones or generating bone tissues. The pathogenicmechanism of osteoporosis can be explained by a subtle bone matrixresulting from long maintenance of negative bone homeostasis due togenetic or constitutional predispositions, stagnant osteogenesis withnormal bone resorption, and increased bone resorption with normalosteogenesis. Osteoporosis agents are, therefore, ineffective for thetreatment of bone fractures because the healing mechanism is quitedifferent between fractures and osteoporosis.

Therefore, there is an urgent need for a bone fracture curative agentthat has great therapeutic effect on bone fractures, regardless ofassociation with osteoporosis

As diverse pathologies associated with environmental pollution, stress,living environments, etc., an allergic inflammatory disease hasincreased. Allergic inflammatory disease is attributed to abnormality inthe immune system where the nasal or bronchial mucosa or skin ishypersensitive to external allergens. Basic causes of allergy includenutrition imbalance, stress, extravasated blood, etc., with the majorcause being nutrition imbalance.

Depending on the site where immune responses occur against exogenousallergens, allergic inflammatory disease is represented as varioussymptoms including allergic rhinitis, asthma, atopic dermatitis, etc. Inaddition, allergic conjunctivitis, allergic dermatitis, contactdermatitis, urticaria, etc. are within the scope of allergicinflammatory diseases. Since these symptoms, although very diverse, arecommon in the pathology based on the hypersensitivity to externallyintroduced matter, a suppressant of excessive immune responses can beprescribed for all of them.

Asthma, representative of allergies, is a chronic inflammatory diseaseoccurring in the respiratory organ, especially, the lungs and thebronchi. When patients with asthma take drugs or excessive exercise orinhale contaminated and/or cold air, their respiratory organs,especially, upper respiratory organs increase in responsiveness. Thishyper-responsiveness is associated with the airflow obstruction in theairway, that is, airway obstruction or tracheal stenosis, but is readilyalleviated using a bronchodilator. Included in the consensuscharacteristics of asthma, hyper-responsiveness to indoor and/or outdoorallergens and airway contraction are known to be mediated by mast cellsand eosinophil IgE (Beasley et al., Am. Rev. Respir. Dis., 129, 806-817,1989).

Asthma is accompanied by the allergic hyper-responsiveness mainly in thebronchia and the lungs. Particularly, the air passage becomes clogged bythe proliferation of mucous cells and the inflammation of epithelialconnective tissues in the bronchia. Alsom the lungs are known to showsimilar histological behaviors. The pathology of asthma, although notyet clearly revealed thus far, is reported to be featured by airwaystenosis, edema, mucus secretion, inflammatory cell infiltration, etc.In the mechanism of a typical exogenous asthma, when an antigen isintroduced into the airway, B cells produce antigen specific antibodiesIgE and IgG in cooperation with macrophages and helper T-cells. Theseantigen specific antibodies bind to receptors on the surfaces of mastcells and basophils, which are then activated upon re-exposure to thesame antigen so as to release various cytokines and mediators ofallergy/inflammation, including histamine, prostaglandin D₂, slowreacting substances (leukotriene C₄, D₄), etc. out of the cells. Due tothese cytokines and mediators, when exposed to aeroallergen, patientswith asthma exhibit an early asthma response characterized by a rapidairway constriction over a period of seconds to minutes and apparentrecovery within 30 to 60 min from the constriction. Then, the mediatorssecreted from mast cells and the cytokines secreted from macrophages,mast cells and helper T-cells proliferate and activate inflammatorycells, including eosinophils, to exhibit a late asthmatic response inwhich bronchoconstriction, mucus secretion and inflammatory cellinfiltration begin 3 to 4 hours and peak 4 to 18 hours after exposure toaeroallergens (Robertson et al., J. Allergy Clin. Immunol., 54, 244-257,1974).

Currently available therapeutic agents for the treatment of asthmainclude beta 2-adreno receptor agonists, which dilate airway smoothmuscles and effectively, inhibit the secretion of hyperresponsivenessmediators from mast cells, adrenal cortical hormones, which exhibit animmunosuppressive effect, and disodium cromoglycate and nedocromilsodium, both known to inhibit both the early and the late asthmaresponse. However, beta 2-adreno receptor antagonists show the treatmenteffect only for a short period of time and allow the ready recurrence ofthe disease. Adrenal cortical hormones have fragmentary treatmenteffects, with the concomitance of serious side effects upon long-termdosage.

Leading to the present invention, intensive and thorough study onosteoporosis, bone fractures and allergic inflammatory diseasesconducted by the present inventors, resulted in the finding that novelbenzamidine derivatives have effects on suppressing the osteoclasticbone resorption and inhibiting the decrease of bone mass in animalmodels, indication the compounds are useful in the prevention andtreatment of osteoporosis; healing bone fractures; and treating andpreventing allergic inflammatory disease.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide novel benzamidinederivatives. Another objective of the present invention is to providetheir preparation method. Further another object of the presentinvention is to provide pharmaceutical compositions for the preventionand treatment of osteoporosis, allergic inflammatory diseases and bonefractures comprising novel benzamidine derivatives.

BEST MODE FOR CARRYING OUT THE INVENTION

The invention relates to novel benzamdine derivatives of the formula 1or pharmaceutically acceptable salts thereof:

wherein

R₁ is C₁˜C₆ alkyl; C₃˜C₆ cycloalkyl; phenyl; benzyl; pyridinyl;guanidino; NR₆R₇; CH₂NR₆R₇;

wherein A is C₁˜C₆ alkyl and n is an integer of 2 to 6; C₁˜C₆ alkylwhich is substituted by pyridine or

wherein

is unsubstituted or substituted by hydroxy; pyridinyl or

which is substituted by C₁˜C₆ alkyl;

R₂ is hydrogen; C₁˜C₆ alkyl; C₃˜C₆ cycloalkyl; phenyl; benzyl; C₁˜C₆alkyl which is substituted by hydroxy, C₁˜C₆ alkoxy, halogen or C₃˜C₆cycloalkyl; C₂˜C₆ alkenyl;

R₃ and R₄, each independently, are hydrogen; halogen; hydroxy; C₁˜C₆alkyl which is unsubstituted or substituted halogen; C₃˜C₆cycloalkylamino; C₁˜C₆ alkoxy; C₁˜C₆ alkanoyloxy; C₂˜C₆ alkenyloxy;phenyl-C₁˜C₆ alkoxy; phenoxy; C₂˜C₆ alkenoyloxy or phenyl-C₁˜C₆alkanoyloxy; C₃˜C₆ cycloalkyloxy which is substituted by carboxy,esterified carboxy or amidated carboxy; aminooxy;

R₅ is hydrogen or hydroxy;

R₆ and R₇, each independently, are hydrogen; C₁˜C₆ alkyl; phenyl;benzyl; pyridinyl; C₁˜C₆alkyl which is substituted by pyridine or

carbonyl which is substituted by C₁˜C₆ alkyl, phenyl, benzyl, pyridineor

C₁˜C₆ alkanesulfonyl; C₁˜C₆ alkyl which is substituted by hydroxy orC₁˜C₆ alkoxy; acetyl which is substituted by hydroxy or C₁˜C₆ alkoxy;

Y is oxygen; sulfur; NR₆; or CH₂;

X₁ and X₃, each independently, are oxygen; sulfur; NH; N—C₁˜C₆ alkyl;N—C₃˜C₆cycloalkyl; N-benzyl; N-phenyl;

X₂ is C₃-C₇ alkylene; C₁-C₃ alkylene-alkenylene-C₁-C₃-alkylene; C₁-C₃alkylene-O—C₁-C₃ alkylene; C₁-C₃ alkylene-S—C₁-C₃ alkylene; C₁-C₃alkylene-NH—C₁-C₃ alkylene; C₁-C₃ alkylene-phenylene-C₁-C₃ alkylene;C₁-C₃ alkylene-pyridylene-C₁-C₃ alkylene; C₁-C₃alkylene-naphtylene-C₁-C₃ alkylene; C₃-C₇ alkylene which is substitutedby C₁-C₃ alkyl and hydroxy; C₃-C₇ alkylenecarbonyl; C₃-C₇ alkylene whichis interrupted by piperazine.

The invention especially relates to compounds of the formula 1 in which:

R₁ is C₁˜-C₆ alkyl; C₃˜C₆ cycloalkyl; phenyl; pyridinyl; guanidino;NR₆R₇; CH₂NR₆R₇;

wherein A is C₁˜C₆ alkyl and n is an integer of 2 to 6; C₁˜C₆ alkylwhich is substituted by

wherein

is unsubstituted or substituted by hydroxy;

which is substituted C₁˜C₆ alkyl;

R₂ is hydrogen; C₁˜C₆ alkyl; C₃˜C₆ cycloalkyl; benzyl; C₁˜C₆ alkyl whichis substituted by hydroxyl, methoxy, halogen or C₃˜C₆ cycloalkyl; C₂˜C₆alkenyl;

R₃ and R₄ each independently, are hydrogen; halogen; hydroxy; C₃˜C₆cycloalkylamino; C₁˜C₆ alkoxy; C₁˜C₆ alkanoyloxy; C₃˜C₆ cycloalkyloxywhich is substituted by carboxy, esterified carboxy or amidated carboxy;aminooxy;

R₅ is hydrogen or hydroxy;

R₆ and R₇ each independently, are hydrogen; C₁˜C₆ alkyl; benzyl;pyridinyl; C₁˜C₆ alkyl which is substituted by pyridine or

carbonyl which is substituted by pyridine or C₁˜C₆ alkyl; C₁˜C₆alkanesulfonyl; C₁˜C₆ alkyl which is substituted by hydroxy or C₁˜C₆alkoxy; acetyl which is substituted by hydroxy or C₁˜C₆ alkoxy;

Y is oxygen; sulfur; NR₆; CH₂;

X₁ and X₃, each independently, are oxygen; sulfur; NH; N—C₁˜C₆ alkyl;

X₂ is C₃-C₇ alkylene; C₁-C₃ alkylene-alkenylene-C₁-C₃-alkylene; C₁-C₃alkylene-O—C₁-C₃ alkylene; C₁-C₃ alkylene-NH—C₁-C₃ alkylene; C₁-C₃alkylene-phenylene-C₁-C₃ alkylene; C₁-C₃ alkylene-pyridylene-C₁-C₃alkylene; C₁-C₃ alkylene-naphtylene-C₁-C₃ alkylene; C₃-C₇ alkylene whichis substituted by C₁-C₃ alkyl or hydroxy; C₃-C₇ alkylenecarbonyl; C₃-C₇alkylene which is interrupted by piperazine.

The invention further especially relates to compounds of the formula 1in which:

R₁ is methyl; ethyl; propyl; isopropyl; butyl; t-butyl; pentyl;cyclopentyl; hexyl; cyclohexyl; phenyl; aminomethyl; aminoethyl; amino;isobutylamide; guanidino; 1-propyl-piperidino; 2-morpholinomethyl;NR₆R₇; CH₂NR₅R₇;

wherein A is C₁˜C₆ alkyl and n is an integer of 2 to 6; pyridinyl;4-hydroxypiperidinomethyl; cyclohexylaminomethyl;

R₂ is hydrogen; methyl; ethyl; isopropyl; propyl; butyl; isobutyl;methoxymethyl; hydroxymethyl; 2-methylpropyl; pentyl; chloromethyl;chloroethyl; cyclopentyl; cyclopentylmethyl; cyclohexyl; benzyl; vinyl;

R₃ and R₄, each independently, are hydrogen; halogen; hydroxy;cyclohexylamino; methoxy; C₁-C₄ alkanoyloxy; C₁-C₇ aliphatic alkoxywhich is substituted by carboxy, esterified carboxy or amidated carboxy;

R₅ is hydrogen or hydroxy;

R₆ and R₇, each independently, are hydrogen; methyl; ethyl; propyl;benzyl; pyridin-3-yl; pyridin-4-yl; 2-morpholinoethyl;4-pyridinylcarbonyl; 3-pyridinylcarbonyl; isobutylcarbonyl;ethanesulfonyl; methoxyethyl; hydroxyethyl; hydroxyacetyl;methoxyacetyl;

Y is oxygen; sulfur; NR₆; CH₂;

X₁ and X₃, each independently, are oxygen; sulfur; amine; methylamine;

X₂ is propylene; butylene; pentylene; hexylene; heptylene;ethylene-O-ethylene; 3-hydroxy-3-methyl-pentylene;methylethylene-NH-ethylene; ethylene-NH-ethylene; propylene which isinterrupted by piperazine; butylene carbonyl; 2-butenyl;methylene-phenylene-methylene; methylene-pyridylene-methylene;1,2-ethylene-1,4-phenylene-1,2-ethylene;1,3-propylene-1,4-phenylene-1,3-propylene;1,2-ethylene-naphthalene-1,2-ethylene.

The invention furthermore especially relates to compounds of the formula1 in which,

R₁ is methyl; ethyl; isopropyl; cyclohexyl; phenyl; aminomethyl;aminoethyl; amino; pyridinyl; NR₆R₇; CH₂NR₆R₇;

wherein A is C₁˜C₂ alkyl and n is an integer of 4 to 5;

R₂ is hydrogen; methyl; ethyl; isopropyl; isobutyl; methoxymethyl;hydroxymethyl; chloromethyl; chloroethyl; cyclopentyl;cyclopentylmethyl; vinyl;

R₃ and R₄, each independently, are hydrogen; halogen; hydroxy; methoxy;

R₅ is hydrogen or hydroxy;

R₆ and R₇, each independently, are hydrogen; methyl; ethyl; benzyl;pyridin-3-yl; pyridin-4-yl; 2-morpholinoethyl; 4-pyridinylcarbonyl;3-pyridinylcarbonyl; isobutylcarbonyl; ethanesulfonyl; hydroxyethyl;methoxyethyl;

Y is oxygen; sulfur; methylamine;

X₁ and X₃, each independently, are oxygen; sulfur; amino; methylamine;

X₂ is propylene; butylene; pentylene; hexylene; ethylene-O-ethylene;ethylene-NH-ethylene; butylenecarbonyl; 2-butenyl;methylene-1,2-phenylene-methylene; methylene-1,3-phenylene-methylene;methylene-1,4-phenylene-methylene; methylene-pyridinyl-methylene.

In the compounds of the formula 1 of the present invention, the—C(NH₂)═N—R₅ group is in the meta or para position, and R₃ and R₄ are inthe ortho or meta position relative to —X₁— or —X₃—.

The preferred compounds of the present invention is described infollowing:

-   1)    N-hydroxy-4-5-[4-(2-isopropyl-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   2)    4-5-[4-(2-isopropyl-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   3)    N-hydroxy-4-5-[4-(2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   4)    N-hydroxy-4-5-[4-(2-ethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   5)    N-hydroxy-4-5-[4-(2-isopropyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   6)    N-hydroxy-4-5-[4-(2-phenyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   7)    N-hydroxy-4-5-[4-(2-pyridin-3-yl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   8)    N-hydroxy-4-5-[4-(2-cyclohexyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   9)    N-hydroxy-4-5-[4-(2-pentyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   10)    N-hydroxy-4-5-[4-(2,5-dimethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   11)    N-hydroxy-4-5-[4-(2-ethyl-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   12)    N-hydroxy-4-5-[4-(5-methyl-2-phenyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   13)    N-hydroxy-4-5-[4-(5-methyl-2-pyridin-3-yl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   14)    N-hydroxy-4-5-[4-(2-cyclohexyl-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   15)    N-hydroxy-4-5-[4-(5-methyl-2-pentyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   16)    N-hydroxy-4-5-[4-(2-t-butyl-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   17)    N-hydroxy-4-5-[4-(5-ethyl-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   18)    N-hydroxy-4-5-[4-(2,5-diethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   19)    N-hydroxy-4-5-[4-(5-ethyl-2-isopropyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   20)    N-hydroxy-4-5-[4-(5-ethyl-2-phenyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   21)    N-hydroxy-4-5-[(4-(5-ethyl-2-pyridin-3-yl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   22)    N-hydroxy-4-5-[4-(2-cyclohexyl-5-ethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   23)    N-hydroxy-4-5-[4-(5-ethyl-2-pentyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   24)    N-hydroxy-4-5-[4-(2-ethyl-5-isopropyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   25)    N-hydroxy-4-5-[4-(2,5-diisopropyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   26)    N-hydroxy-4-5-[4-(5-isopropyl-2-phenyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   27)    N-hydroxy-4-5-[4-(5-isopropyl-2-pyridin-3-yl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   28)    N-hydroxy-4-5-[4-(5-isopropyl-2-pentyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   29)    N-hydroxy-4-5-[4-(2-methyl-5-propyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   30)    N-hydroxy-4-5-[4-(5-butyl-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   31)    N-hydroxy-4-5-[4-(5-butyl-2-ethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   32)    N-hydroxy-4-5-[4-(5-butyl-2-isopropyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   33)    N-hydroxy-4-5-[4-(5-butyl-2-phenyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   34)    N-hydroxy-4-5-[4-(5-butyl-2-pyridin-3-yl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   35)    N-hydroxy-4-5-[4-(5-butyl-2-cyclohexyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   36)    N-hydroxy-4-5-[4-(5-butyl-2-pentyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   37)    N-hydroxy-4-5-[4-(5-butyl-2-t-butyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   38)    N-hydroxy-4-5-[4-(5-benzyl-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   39)    N-hydroxy-4-5-[4-(5-benzyl-2-isopropyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   40)    N-hydroxy-4-5-[4-(5-benzyl-2-phenyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   41)    N-hydroxy-4-5-[4-(5-benzyl-2-pyridin-3-yl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   42)    N-hydroxy-4-5-[4-(5-(2-chloro-ethyl)-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   43)    N-hydroxy-4-5-[4-(5-cyclopentyl-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   44)    N-hydroxy-4-5-[4-(5-isobutyl-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   45)    N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   46)    N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-ethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   47)    N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-isopropyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   48)    N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-phenyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   49)    N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-pyridin-3-yl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   50)    N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-cyclohexyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   51)    N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-pentyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   52) 4-5-[4-(2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   53)    4-5-[4-(2-isopropyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   54)    4-5-[4-(2,5-dimethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   55)    4-5-[4-(5-ethyl-2-isopropyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   56)    4-5-[4-(5-ethyl-2-phenyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   57)    N-hydroxy-4-5-[4-(2-amino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   58)    N-hydroxy-4-5-[4-(2-amino-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   59)    N-hydroxy-4-5-[4-(2-guanidino-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   60)    N-hydroxy-4-5-[4-(2-amino-5-ethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   61)    N-hydroxy-4-5-[4-(2-amino-5-isopropyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   62)    N-hydroxy-4-5-[4-(2-guanidino-5-isopropyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   63)    N-hydroxy-4-5-[4-(2-amino-5-butyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   64)    N-hydroxy-4-5-[4-(5-butyl-2-guanidino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   65)    N-hydroxy-4-5-[4-(2-amino-5-benzyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   66)    N-hydroxy-4-5-[4-(5-benzyl-2-guanidino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   67)    N-hydroxy-4-5-[4-(2-amino-5-cyclopentylmethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   68)    N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-(1-propyl-piperidin-4-yl)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   69)    N-hydroxy-4-5-[4-(2-(isobutyryl)amino-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine-   70)    N-hydroxy-4-5-[4-(5-isopropyl-2-morpholinomethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   71)    N-hydroxy-4-5-[4-(2-aminomethyl-5-benzyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   72)    N-hydroxy-4-5-[4-(5-methyl-2-(1-propyl-piperidin-4-yl)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   73)    N-hydroxy-4-5-[4-(5-isopropyl-2-aminomethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   74)    N-hydroxy-4-5-[4-(5-vinyl-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   75)    N-hydroxy-4-5-[4-(5-hydroxymethyl-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   76)    N-hydroxy-4-5-[4-(5-methoxymethyl-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   77)    N-hydroxy-4-5-[4-(5-(2-chloroethyl)-2-amino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   78)    N-hydroxy-4-5-[4-(5-vinyl-2-amino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   79)    N-hydroxy-4-5-[4-(5-vinyl-2-(pyridin-3-yl)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   80)    N-hydroxy-4-5-[4-(5-(2-chloroethyl)-2-(pyridin-3-yl)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   81)    N-hydroxy-4-5-[4-(2-amino-5-cyclopentyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   82)    N-hydroxy-4-5-[4-(5-ethyl-2-aminomethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   83)    N-hydroxy-4-5-[4-(5-isopropyl-2-(piperidin-3-yl)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   84)    N-hydroxy-4-5-[4-(2-ethylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   85)    N-hydroxy-4-5-[4-(2-ethanesulfonylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   86)    N-hydroxy-4-5-[4-(5-methyl-2-methylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   87)    N-hydroxy-4-5-[4-(2-ethylamino-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   88)    N-hydroxy-4-5-[4-(5-methyl-2-propylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   89)    N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-(3-pyridylcarbonyl)amino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   90)    N-hydroxy-4-5-[4-(2-hydroxyacetylamino-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   91)    N-hydroxy-4-5-[4-(5-methyl-2-(4-pyridylcarbonyl)amino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   92)    N-hydroxy-4-5-[4-(5-methyl-2-(3-pyridylcarbonyl)amino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   93)    N-hydroxy-4-5-[4-(2-ethanesulfonylamino-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   94)    N-hydroxy-4-5-[4-(2-(2-methoxyethyl)amino-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   95)    N-hydroxy-4-5-[4-(2-ethanesulfonylamino-5-ethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   96)    N-hydroxy-4-5-[4-(5-ethyl-2-methylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   97)    N-hydroxy-4-5-[4-(5-ethyl-2-ethylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   98)    N-hydroxy-4-5-[4-(5-ethyl-2-propylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   99)    N-hydroxy-4-5-[4-(5-ethyl-2-methoxyacetylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   100)    N-hydroxy-4-5-[4-(5-ethyl-2-(4-pyridylcarbonyl)amino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   101)    N-hydroxy-4-5-[4-(5-ethyl-2-(3-pyridylcarbonyl)amino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   102)    N-hydroxy-4-5-[4-(5-ethyl-2-(2-methoxyethyl)amino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   103)    N-hydroxy-4-5-[4-(5-isopropyl-2-methylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   104)    N-hydroxy-4-5-[4-(2-ethylamino-5-isopropyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   105)    N-hydroxy-4-5-[4-(5-butyl-2-methylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   106)    N-hydroxy-4-5-[4-(5-butyl-2-ethylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   107)    N-hydroxy-4-5-[4-(5-benzyl-2-methylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   108)    N-hydroxy-4-5-[4-(5-benzyl-2-ethylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   109)    N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-methylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   110)    N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-ethylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   111)    N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-propylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   112)    N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-(4-pyridylcarbonyl)amino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   113)    N-hydroxy-4-5-[4-(5-cyclopentyl-2-propylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   114)    N-hydroxy-4-5-[4-(5-isopropyl-2-[(pyridin-3-yl-methyl)amino]-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   115)    N-hydroxy-4-5-[4-(5-(2-chloroethyl)-2-methylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   116)    N-hydroxy-4-5-[4-(2-methylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   117)    N-hydroxy-4-5-[4-(5-ethyl-2-[(pyridin-3-yl-methyl)amino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   118)    N-hydroxy-4-5-[4-(2-(ethanesulfonyl-methyl-amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   119)    N-hydroxy-4-5-[4-(2-methyl-(2-morpholinoethyl)amino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   120)    N-hydroxy-4-5-[4-(2-(2-hydroxyethyl)-methyl-amino-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   121)    N-hydroxy-4-5-[4-(2-(ethyl-(2-hydroxyethyl)-amino)-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   122)    N-hydroxy-4-5-[4-(2-(bis-(2-methoxyethyl)-amino)-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   123)    N-hydroxy-4-5-[4-(5-methyl-2-(methyl-(2-morpholinoethyl)-amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   124)    N-hydroxy-4-5-[4-(2-(ethyl-1-(2-morpholinoethyl)-amino)-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   125)    N-hydroxy-4-5-[4-(2-(benzyl-methyl-amino)-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   126)    N-hydroxy-4-5-[4-(5-methyl-2-(methyl-pyridin-3-yl-methyl-amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   127)    N-hydroxy-4-5-[4-(2-(benzyl-ethyl-amino)-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   128)    N-hydroxy-4-5-[4-(2-(bis-(2-hydroxyethyl)-amino)-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   129)    N-hydroxy-4-5-[4-(5-ethyl-2-((2-hydroxyethyl)-methyl-amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   130)    N-hydroxy-4-5-[4-(5-ethyl-2-(ethyl-(2-hydroxyethyl)-amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   131)    N-hydroxy-4-5-[4-(5-ethyl-2-(methyl-(2-morpholinoethyl)-amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   132)    N-hydroxy-4-5-[4-(5-ethyl-2-(ethyl-(2-morpholinoethyl)-amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   133)    N-hydroxy-4-5-[4-(2-(benzyl-methyl-amino)-5-ethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   134)    N-hydroxy-4-5-[4-(5-ethyl-2-(methyl-(pyridin-3-yl-methyl)amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   135)    N-hydroxy-4-5-[4-(2-(benzyl-ethyl-amino)-5-ethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   136)    N-hydroxy-4-5-[4-(5-ethyl-2-(ethyl-(pyridin-3-yl-methyl)amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   137)    N-hydroxy-4-5-[4-(2-(bis-(pyridin-3-yl-methyl)amino)-5-ethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   138)    N-hydroxy-4-5-[4-(2-dipropylamino-5-ethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   139)    N-hydroxy-4-5-[4-(2-(bis-(2-hydroxyethyl)amino)-5-ethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   140)    N-hydroxy-4-5-[4-(2-((2-hydroxyethyl)-methyl-amino)-5-isopropyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   141)    N-hydroxy-4-5-[4-(5-isopropyl-2-(methyl-(pyridin-3-yl-methyl)amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   142)    N-hydroxy-4-5-[4-(2-(ethanesulfonyl-methyl-amino)-5-isopropyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   143)    N-hydroxy-4-5-[4-(5-butyl-2-((2-hydroxyethyl)-methyl-amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   144)    N-hydroxy-4-5-[4-(5-butyl-2-(methyl-(2-morpholinoethyl)amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   145)    N-hydroxy-4-5-[4-(5-butyl-2-(methyl-(pyridin-3-yl-methyl)amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   146)    N-hydroxy-4-5-[4-(5-butyl-2-dipropylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   147)    N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-(methyl-(pyridin-3-yl-methyl)amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   148)    N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-(methyl-(2-morpholinoethyl)amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   149)    N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-dipropylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   150)    N-hydroxy-4-5-[4-(5-butyl-2-diethylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   151)    N-hydroxy-4-5-[4-(5-butyl-2-ethylmethylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   152)    N-hydroxy-4-5-[4-(5-butyl-2-dimethylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   153)    N-hydroxy-4-[5-(4-5-cyclopentyl-2-[methyl-(2-morpholinoethyl)amino]-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   154)    N-hydroxy-4-[5-(4-5-isobutyl-2-[methyl-(2-morpholinoethyl)amino]-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   155)    N-hydroxy-4-5-[4-(5-(2-chloroethyl)-2-dimethylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   156)    N-hydroxy-4-5-[4-(5-cyclopentyl-2-diethylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   157)    N-hydroxy-4-5-[4-(5-isopropyl-2-dipropylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   158)    N-hydroxy-4-5-[4-(5-ethyl-2-diethylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   159)    N-hydroxy-4-[5-(4-5-isopropyl-2-[methyl-(2-morpholinoethyl)amino]-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   160)    N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-diethylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   161)    N-hydroxy-4-5-[4-(5-isopropyl-2-dimethylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   162)    N-hydroxy-4-5-[4-(5-isopropyl-2-diethylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   163)    N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-dimethylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   164)    N-hydroxy-4-5-[4-(5-methyl-2-piperidino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   165)    N-hydroxy-4-5-[4-(5-methyl-2-morpholino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   166)    N-hydroxy-4-5-[4-(5-ethyl-2-piperidino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   167)    N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-piperidino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   168)    N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-morpholino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   169)    N-hydroxy-4-5-[4-(5-isopropyl-2-morpholino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine-   170)    N-hydroxy-4-5-4-[5-cyclopentylmethyl-2-(4-methylpiperazino)-1,3-thiazol-4-yl]phenoxy-pentoxy-benzamidine,-   171)    N-hydroxy-4-5-[4-(5-vinyl-2-morpholin-4-yl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   172)    N-hydroxy-4-5-[4-(5-cyclopentyl-2-morpholin-4-yl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   173)    N-hydroxy-4-5-[4-(5-isobutyl-2-morpholin-4-yl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   174)    N-hydroxy-4-5-4-[5-ethyl-2-(4-methylpiperazino)-1,3-thiazol-4-yl]phenoxy-pentoxy-benzamidine,-   175)    N-hydroxy-4-5-[4-(2-morpholin-4-yl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,-   176)    N-hydroxy-4-5-4-[5-isopropyl-2-(4-methylpiperazino)-1,3-thiazol-4-yl]phenoxy-pentoxy-benzamidine,-   177)    N-hydroxy-4-5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)phenoxy]-pentylamino-benzamidine,-   178)    N-hydroxy-4-2-[2-(4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)phenoxy)-ethoxy]-ethoxy-benzamidine,-   179)    N-hydroxy-4-3-hydroxy-5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)-phenoxy]-3-methyl-pentoxy-benzamidine,-   180)    N-hydroxy-4-2-[2-(4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)-phenoxy)-1-methyl-ethylamino]-ethoxy-benzamidine,-   181)    N-hydroxy-4-3-[4-(3-(4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)-phenoxy)-propyl)-piperazin-1-yl]-propoxy-benzamidine,-   182)    N-hydroxy-4-5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)-phenoxy]-pentanoyl-amino-benzamidine,-   183)    N-hydroxy-4-5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)-phenoxy]-pentyl-methyl-amino-benzamidine,-   184)    N-hydroxy-4-4-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)-phenoxy]-2-butenyloxy-benzamidine,-   185)    N-hydroxy-4-4-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)-phenoxymethyl]-benzyloxy-benzamidine,-   186)    N-hydroxy-4-2-[2-(4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)phenoxy)-ethylamino]-ethoxy-benzamidine,-   187)    N-hydroxy-2-fluoro-4-5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)-phenoxy]-pentoxy-benzamidine,-   188)    2,N-dihydroxy-4-5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)-phenoxy]-pentoxy-benzamidine,-   189)    N-hydroxy-4-5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)-phenoxy]-pentoxy-3-methoxy-benzamidine,-   190)    N-hydroxy-2-cyclohexylamino-4-5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)-phenoxy]-pentoxy-benzamidine,-   191)    N-hydroxy-4-5-[3-fluoro-4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)-phenoxy]-pentoxy-benzamidine,-   192)    N-hydroxy-2-fluoro-4-5-[3-fluoro-4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)-phenoxy]-pentoxy-benzamidine,-   193)    N-hydroxy-4-3-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)phenoxy]propoxy-benzamidine,-   194)    N-hydroxy-4-4-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)phenoxy]butoxy-benzamidine,-   195)    N-hydroxy-3-5-[4-(5-isopropyl-2-methyl-thiazol-4-yl)-phenoxy]-pentylamino-benzamidine,-   196)    N-hydroxy-4-4-[4-(2-cyclohexyl-5-ethyl-thiazol-4-yl)-phenoxy]-butoxy-benzamidine,-   197)    N-hydroxy-4-[5-(4-5-ethyl-2-[(2-hydroxyethyl)-methyl-amino]-thiazol-4-yl)phenoxy]propoxy-benzamidine,-   198)    N-hydroxy-4-[5-(4-5-ethyl-2-[(2-hydroxyethyl)-methyl-amino]-thiazol-4-yl)phenoxy]butoxy-benzamidine,-   199)    N-hydroxy-4-[5-(4-5-ethyl-2-[methyl-(pyridin-3-yl-methyl)amino]-thiazol-4-yl)phenoxy]propoxy-benzamidine,-   200)    N-hydroxy-4-[5-(4-5-ethyl-2-[methyl-(pyridin-3-yl-methyl)amino]-thiazol-4-yl)phenoxy]butoxy-benzamidine,-   201)    N-hydroxy-4-4-[4-(5-cyclopentylmethyl-2-isopropyl-thiazol-4-yl)-phenoxymethyl]-benzyloxy-benzamidine,-   202)    N-hydroxy-4-4-[4-(5-butyl-2-isopropyl-thiazol-4-yl)-phenoxymethyl]-benzyloxy-benzamidine,-   203)    N-hydroxy-4-4-[4-(5-cyclopentylmethyl-2-amino-thiazol-4-yl)-phenoxymethyl]-benzyloxy-benzamidine,-   204)    N-hydroxy-4-4-[4-(5-cyclopentylmethyl-2-amino-thiazol-4-yl)-phenoxymethyl]-benzyloxy-2-fluoro-benzamidine,-   205)    N-hydroxy-4-4-[4-(2-methylamino-thiazol-4-yl)-phenoxymethyl]-benzyloxy-benzamidine,-   206)    N-hydroxy-4-6-[4-(5-isopropyl-2-methyl-thiazol-4-yl)-phenoxymethyl]-pyridin-2-yl-methoxy-benzamidine,-   207)    N-hydroxy-2-fluoro-4-5-[4-(5-isopropyl-2-methyl-thiazol-4-yl)-phenoxy]-butoxy-benzamidine,-   208)    N-hydroxy-4-2-[4-(5-isopropyl-2-methyl-thiazol-4-yl)-phenoxymethyl]-benzyloxy-benzamidine,-   209)    N-hydroxy-4-3-[4-(5-isopropyl-2-methyl-thiazol-4-yl)-phenoxymethyl]-benzyloxy-benzamidine,-   210)    N-hydroxy-4-4-[4-(5-cyclopentylmethyl-2-cyclohexyl-thiazol-4-yl)-phenoxymethyl]-benzyloxy-benzamidine,-   211)    N-hydroxy-4-6-[4-(5-isopropyl-2-methyl-thiazol-4-yl)phenoxy]-hexyloxy-benzamidine,-   212)    N-hydroxy-4-5-[2-ethyl-5-hydroxy-4-(2-methyl-thiazol-4-yl)phenoxy]-pentyloxy-benzamidine,-   213)    N-hydroxy-4-5-[2-ethyl-4-(2-methyl-thiazol-4-yl)-5-propoxy-phenoxy]-pentyloxy-benzamidine.

The benzamidine derivatives of the formula 1 may be used in the form ofpharmaceutically acceptable salts known in the art. Preferable are acidaddition salts prepared with pharmaceutically acceptable free acids.Free acids suitable for use in the present invention may be inorganicacids or organic acids. Examples of the inorganic acids includehydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, etc, andthe organic acids may be exemplified by citric acid, acetic acid, lacticacid, tartaric acid, fumaric acid, formic acid, propionic acid, oxalicacid, trifluoroacetic acid, methane sulfonic acid, benzene sulfonicacid, maleic acid, maleinic acid, benzoic acid, gluconic acid, glycolicacid, succinic acid, 4-morpholine ethane sulfonic acid, camphorsulfonicacid, 4-nitrobenzene sulfonic acid, hydroxy-O-sulfonic acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, asparticacid, etc. Preferably, hydrochloric acid as inorganic acid and methanesulfonic acid as organic acid can be used.

General definitions of substituted groups of the formula 1 have thefollowing meanings:

Halogen means halogen group atoms including chlorine, fluorine, bromine,iodine, etc.

Alkyl radical means saturated carbohydrogens which have 1 to 6 carbonatoms and are straight or branched, for example, methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, etc.

Alkoxy radical means said alkyl radical linked to oxygen, for example,methoxy, ethoxy, propoxy, iso-propoxy, butoxy, sec-butoxy, tert-butoxy,etc.

Cycloalkyl radical means nonaromatic carbohydrogen ring(s) which have 3to 6 carbon atoms on the each ring, for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, etc.

Alkenyl radical means unsaturated carbohydrogens which have 2 to 6carbon atoms with one or more double bonds.

Alkanoyloxy radical means oxygen-containing radical in which a terminalcarbon atom of alkyl radical is substituted by carbonyl radical.

Alkenoyloxy radical means oxygen-containing radical in which a terminalcarbon atom of alkenyl radical is substituted by carbonyl radical.

Alkenyloxy radical means oxygen-containing alkenyl groups.

Alkylene radical means carbohydrogen radicals which have 1 to 7 carbonatoms and 2 or more junction centers for covalent bond, includingmethylene, ethylene, methylethylene, isopropylidene, etc.

Alkenylene radical means carbohydrogen radicals which have 2 to 7 carbonatoms, 2 or more conjunction centers for covalent bond and 1 or moredouble bonds, including 1,1-vinylidene (CH₂═C), 1,2-vinylidene(—CH═CH—), 1,4-butadienyl (—CH═CH—CH═CH, etc.

Carbonyl radical means carbon radicals in which 2 of 4 covalent bondsare linked to oxygen atom.

In another aspect, the present invention provides a method of preparingbenzamidine derivatives of the formula 1 below:

If R₁ is C₁˜C₆ alkyl; pyridine-substituted C₁˜C₆ alkyl; C₃˜C₆cycloalkyl; benzyl; phenyl; amino; guanidino; pyridinyl; pyridinyl whichis substituted by C₁˜C₆ alkyl; or

(A is C₁˜C₆ alkyl and n is integer of 2 to 6), benzamidine derivativesof the formula 1 can be prepared with Reaction Scheme 1 below comprisingthe steps of:

1) reacting a compound of the formula 2 with a compound of the formula 3in the presence of inorganic base to prepare a compound of the formula4,

2) reacting a compound of the formula 5 with acid chloride of theformula 6 in the presence of inorganic acid to prepare phenone of theformula 7, and reacting the phenone of the formula 7 with acid toprepare a compound of the formula 8,

3) reacting the compound of the formula 4 prepared in step 1) with thecompound of the formula 8 prepared in step 2) in the presence ofinorganic base to prepare benzonitrile derivatives of the formula 9,

4) reacting the compound of the formula 9 prepared in step 3) withbrominating agent to prepare α-brominated compound of the formula 10,

5) reacting α-brominated compound of the formula 10 prepared in step 4)with thioamide compound of the formula 11 to prepare benzonitrilederivatives with thiazole ring of the formula 12, and

6) reacting the compound of the formula 12 prepared in step 5) withamine compound to prepare benzamidine derivatives of the formula 1a.

wherein R₂, R₃, R₄, R₅, X₁, X₂ and X₃ are the same as defined in thecompound of the formula 1.

If R₁ is CH₂NHR₆ or NHR₆ (except that R₆ is hydrogen), the compound ofthe formula 1 can be prepared with Reaction Scheme 2 below, comprisingthe steps of:

1) reacting a compound of the formula 2 with a compound of the formula 3in the presence of inorganic base to prepare a compound of the formula4,

2) reacting a compound of the formula 5 with acid chloride of theformula 6 in the presence of inorganic acid to prepare phenone of theformula 7, and reacting the phenone of the formula 7 with acid toprepare a compound of the formula 8,

3) reacting the compound of the formula 4 prepared in step 1) with thecompound of the formula 8 prepared in step 2) in the presence ofinorganic base to prepare benzonitrile derivatives of the formula 9,

4) reacting the compound of the formula 9 prepared in step 3) withbrominating agent to prepare α-brominated compound of the formula 10,

5) reacting α-brominated compound of the formula 10 prepared in step 4)with thiourea of the formula 13 to prepare benzonitrile derivatives withaminothiazole ring of the formula 14,

6) reacting the compound of the formula 14 prepared in step 5) withhalide compound of the formula 15 to prepare benzonitrile derivativeswith thiazole ring substituted with primary amine of the formula 16, and

7) reacting the compound of the formula 16 prepared in step 6) withamine compound to prepared benzamidine derivatives of the formula 1b.

wherein R₂, R₃, R₄, R₅, R₆, X₁, X₂ and X₃ are the same as defined in thecompound of the formula 1 and n is an integer of 0 to 6, except that R₆is hydrogen.

If R₁ is CH₂NR₆R₇ or NR₆R₇ (except that R₆ or/and R₇ are hydrogen), thecompound of the formula 1 can be prepared with Reaction Scheme 3 below,comprising the steps of:

1) reacting a compound of the formula 2 with a compound of the formula 3in the presence of inorganic base to prepare a compound of the formula4,

2) reacting a compound of the formula 5 with acid chloride of theformula 6 in the presence of inorganic acid to prepare phenone of theformula 7, and reacting the phenone of the formula 7 with acid toprepare a compound of the formula 8,

3) reacting the compound of the formula 4 prepared in step 1) with thecompound of the formula 8 prepared in step 2) in the presence ofinorganic base to prepare benzonitrile derivatives of the formula 9,

4) reacting the compound of the formula 9 prepared in step 3) withbrominating agent to prepare α-brominated compound of the formula 10,

5) reacting α-brominated compound of the formula 10 prepared in step 4)with thiourea of the formula 13 to prepare benzonitrile derivatives withaminothiazole ring of the formula 14,

6) reacting the compound of the formula 14 prepared in step 5) withhalide compound of the formula 15 to prepare benzonitrile derivativeswith thiazole ring substituted with primary amine of the formula 16,

7) reacting the compound of the formula 16 prepared in step 6) abovewith a compound of the formula 17 to prepare benzonitrile derivativeswith thiazole ring substituted with secondary amine of the formula 18,and

8) reacting the compound of the formula 18 prepared in step 7) withamine compound to prepare benzamidine derivatives of the formula 1c.

wherein R₂, R₃, R₄, R₅, R₆, R₇, X₁, X₂ and X₃ are the same as defined inthe compound of the formula 1 and n is an integer of 0 to 6, except thatR₆/R₇ are hydrogen.

If R₁ is

or C₁˜C₆ alkyl radical substituted by

the compound of the Formula 1 can be prepared with Reaction Scheme 4below, comprising the steps of:

1) reacting a compound of the formula 2 with a compound of the formula 3in the presence of inorganic base to prepare a compound of the formula4,

2) reacting a compound of the formula 5 with acid chloride of theformula 6 in the presence of inorganic acid to prepare phenone of theformula 7, and reacting the phenone of the formula 7 with acid toprepare a compound of the formula 8,

3) reacting the compound of the formula 4 prepared in step 1) with thecompound of the formula 8 prepared in step 2) in the presence ofinorganic base to prepare benzonitrile derivatives of the formula 9,

4) reacting the compound of the formula 9 prepared in step 3) withbrominating agent to prepare α-brominated compound of the formula 10,

5) reacting α-brominated compound of the formula 10 prepared in step 4)with thiourea of the formula 13 to prepare benzonitrile derivatives withaminothiazole ring of the formula 14,

6) reacting the compound of the formula 14 prepared in step 5) with thecompound of which both terminals are halogenated of the formula 19 toprepare benzonitrile derivatives with thiazole ring substituted withhetero atom ring of the formula 20, and

7) reacting the compound of the formula 20 prepared in step 6) withamine compound to prepare benzamidine derivatives of the formula 1d.

wherein R₂, R₃, R₄, R₅, X₁, X₂ and X₃ are the same as defined in thecompound of the formula 1 and n is an integer of 0 to 6.

Each step for preparing benzamidine compounds substituted with thiazolederivative of the present invention, is specifically described below:

In Reaction Scheme 1 to 4, the compound 2, the compound 5, the acidchloride 6, the compound 4, the compound 8, the thioamide 11, thethiourea 13, the halide compound (15, 17), the compound 19 of which bothterminals are substituted with halogen are commercially available or canbe prepared using the method well known in the art.

Reaction Scheme 1 is illustrated by using specific compounds as shownbelow.

In step 1-1, 4-hydroxy-benzonitrile (2; R₄=H, X₃=O) is reacted with1-bromo-5-chloropentane (3; Br—X₂—Cl: X₂=pentylene), giving4-(5-chloro-pentoxy)-benzonitrile (4). The reaction temperature ispreferably maintained in the range of 10 to 90° C., for 1 to 9 hours andthe reaction solvent is acetonitrile, dimethylformamide, etc. To ensurethat the above reaction occurs under a basic condition, an inorganicbasic compound such as potassium carbonate, sodium hydroxide, sodiumhydride, etc, may be used.

In step 1-2, anisole (5; R₃=H, X₁=O) is reacted with propionyl chloride(6; R₂=CH₃) in the presence of inorganic acid to afford phenone compound(7) and phenone compound (7) is consequently reacted in acidic conditionto afford phenol compound (8). Acid chloride (6) used for preparingcompound (7) is a material to introduce substituent R₂ into the compoundof the formula 1 and can be selected from acid chlorides with properalkyl radical according to the type of substituents. These acid chloride(6) includes acetyl chloride, propionyl chloride, butyryl chloride,valeryl chloride, isovaleryl chloride, 4-methylvaleryl chloride,3-methylvaleryl chloride, hexanoyl chloride, cyclopentyryl chloride,chlorobutyl chloride, 3-bromopropionyl chloride, 2,3-dichloropropionylchloride, 4-chlorobutyryl chloride, 3-cyclopentylpropionyl chloride,hydrocinnamoyl chloride, cyclopentylacetyl chloride, isocaproicchloride, which are available commercially or prepared simply withpublic methods. Inorganic acid can be aluminum chloride and the reactioncan be carried out in the range of −20 to 30° C. for 2 to 24 hours. Thereaction solvent can be selected from dichloromethane, chloroform, etc.Acids used for preparing compound (8) are organic acid such as aceticacid and inorganic acid such as bromic acid and aluminum chloride. Thereaction is preferably carried out in the range of 60 to 100° C. for 10to 30 hours. To increase efficiency of the reaction, excess amount ofacid can be used as solvent.

In step 1-3, 4-(5-chloropentoxyl)benzonitrile (4) prepared in step 1-1is reacted with phenol compound (8) prepared in step 1-2 in the presenceof base, thus preparing 4-(5-phenoxypentoxyl)benzonitrile compound (9).Inorganic bases can be used in this reaction, and selected form thegroup of potassium carbonate, sodium hydroxide and sodium hydride. Thereaction can be carried out in the range of 10 to 90° C. for 1 to 9hours and acetonitrile or dimethyl formamide are preferably used as assolvent.

In step 1-4, compound (9) prepared in step 1-3 is reacted withbrominating agent, thus preparing α-brominated compound (10).brominating agent for the reaction can include copper (II) bromide,bromine, etc. and the reaction can be carried out in the range of 20 to80° C. for 8 to 24 hours and ethyl acetate is preferably used assolvent.

In step 1-5, α-brominated compound (10) prepared in step 1-4 is reactedwith thioamide (11), thus preparing compound (12) which has thiazolering. In the reaction, thioamide (11) is a material to introducesubstituent R₁ into the compound of formula 1 and can be selectedaccording to their substituent radical. Reaction time and solvent varyaccording to thioamide compound (11), but in most case, the reaction canbe carried out in the range of 60 to 90° C. for 5 to 24 hours. Thioamidecompound (11) used for the reaction includes thioacetamide,thiopropionamide, thioisobutramide, trimethylthioacetamide,thiohexanoamide, cyclohexancarbothioicacid amide,N-(2-amino-2-thioxoethyl)-2-methylpropanamide, piperidin-4-carbothioicacid amide, thiourea, amidinothiourea, thiobenzoamide, glycinethioamide, 2,2-dimethyl thiopropionamide, which are availablecommercially or prepared simply with public methods. Ethanol orethanol/water mixture is used as a solvent.

In step 1-6, compound (12) which has thiazole ring, prepared in step1-5, is reacted with amine compound in the presence of bases, thuspreparing compound (1a). In the case of N-hydroxy amidine (R₅=OH),hydroxylamine hydrochloride is reacted in the presence of a base, andthe base can be selected from organic bases such as triethylamine,1,8-diazabicyclo[5.4.0]undec-7-ene, DBU, diethylmethylamine (Et₂NMe),N-methylmorpholine, N-methylpiperidine, pyridine and2,6-dimethylpyridine, and inorganic bases such as potassium carbonate,potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodiumamide, sodium hydride, sodium methoxide, sodium ethoxide. The reactionis carried out in the range of 60 to 90° C. for 1 to 15 hrs. Methanol,ethanol, acetonitrile, etc., or their mixture with water can be used asa solvent.

In the case of amidine (R₅=H), methoxy imine is prepared fromhydrocholide methanol solution in the range of 10 to 30° C. for 24 to 48hours and then methanol is evaporated in vacuum condition. The resultantis reacted with ammonia ethanol solution in the range of 45 to 60° C.for 24 to 50 hours in high pressure reactor, finally preparing targetamidines. Ethanol is preferably used as a solvent.

Reaction Scheme 2 is illustrated by using specific compounds as shownbelow.

Steps 2-1 to 2-4 in Reaction Scheme 2 are the same as those in ReactionScheme 1.

In step 2-5, α-brominated compound (10) prepared in step 2-4 is reactedwith thiourea (13), thus preparing benzonitrile compound (14) which hasaminothiazole radical. In the reaction, thiourea (13) is a material tointroduce substituent R₁ into the compound of the formula 1 and can beselected from thioureas with proper alkyl radical according to the typeof substitutents. Reaction time and solvent vary according to the typeof thiourea (13) selected which is available commercially or prepared inpublic methods. The reaction can be preferably carried out in the rangeof 60 to 90° C. for 5 to 24 hours preferentially. Ethanol orEthanol/water mixture can be preferably used as a solvent.

In step 2-6, benzonitrile compound (14) which has aminothiazole radicalprepared in step 2-5, is reacted with halide compound (15) in thepresence of bases, thus preparing benzonitrile compound (16) which hasthiazol ring substituted with amine. In the reaction, halide compound(15) is a material to introduce a substitutents into the amino group ofthe compound of the formula 1 of which the substituent R₁ is primaryamine. Halide compound (15) can be selected according to theirsubstituent radical. Reaction time and solvent vary according toselecting halide compound (15). The reaction can be preferably carriedout in the range of 0 to 90° C. for 5 to 24 hours. Halide compound (15)can includes methyl iodide, ethyl iodide, propyl bromide,2-chloroethylmethyl ether, chloroethyl morpholine,3-bromomethylpyridine, bromoethanol, niconoylchloride, benzyl bromide,nicotinoyl chloride, ethanesulfonyl chloride, isoniconoyl chloride,bis-dibromide ethylester, acetoxyacetyl chloride, methoxyacetylchloride, etc., which are commercially available or prepared in publicmethods. Acetonitrile or dimethylformamide can be preferably used as asolvent.

In step 2-7, benzonitrile compound (16) which has thiazol ringsubstituted with the primary amine, prepared in step 2-6, is reactedwith amine compound in the same condition as that of step 1-6, thuspreparing the compound of the formula 1.

Reaction Scheme 3 is illustrated by using specific compound as shownbelow.

Steps 3-1 to 3-6 in Reaction Scheme 3 are the same as those in ReactionScheme 2.

In step 3-7, compound (16) prepared in step 3-6 is reacted with halidecompound (17) in the presence of base, thus preparing benzonitrilecompound (18) which has thiazole ring substituted with secondary amine.In the reaction, halide compound (17) is a material to introduce thesecond substituent into the amino group of the compound of the formula 1of which the substituent R₁ is the secondary amine. Halide compound (17)can be selected according to its substituent radical. Reaction time andsolvent vary according to selecting the halide compound (17) selected.The reaction can be preferably carried out in the range of 0 to 90° C.for 5 to 24 hours. Halide compound (17) can include methyl iodide, ethyliodide, propyl bromide, 2-chloroethylmethyl ether, chloroethylmorpholine, 3-bromomethylpyridine, bromoethanol, niconoylchloride,benzyl bromide, nicotinoyl chloride, ethanesulfonyl chloride,isoniconoyl chloride, etc., which are commercially available or preparedin public methods. Acetonitrile or dimethylformamide can be preferablyused as a solvent.

In step 3-8, benzonitrile compound (16) which has thiazol ringsubstituted with the secondary amine, prepared in step 3-7, is reactedwith amine compound in the same condition as that of step 1-6, thuspreparing the compound of the formula 1.

Reaction Scheme 4 is illustrated by using specific compounds as shownbelow.

Steps 4-1 to 4-5 in Reaction Scheme 4 are the same as those in ReactionScheme 2.

In step 4-6, benzonitrile compound (14), which has aminothiazole,prepared in step 4-5, is reacted with the compound (19) of which bothterminals are substituted by halogen in the presence of base, thuspreparing benzonitrile compound (20) which has thiazole ring substitutedwith hetero ring. In the reaction, compound (19) is a material tointroduce

into the substituent R₁ of the compound of the formula 1 and can beselected according to its substituents. The reaction can be carried outin the range of 0 to 90° C. for 4 to 24 hours. These halogenatecompounds can include mechloethylamine, bisdibromide ethylester,1,5-dibomopentane, etc., which are commercially available or prepared inpublic methods. Acetonitrile or dimethylformamide can be used as asolvent.

In step 4-7, benzonitrile compound (20) which has thiazole ringsubstituted with hetero ring, prepared in step 4-6, is reacted with theamine compound in the same condition ss that of step 1-6, thus preparingthe compound of the formula 1.

In further aspect, the invention relates to a pharmaceutical compositionfor the prevention and treatment of osteoporosis, allergic inflammatorydiseases and bone fracture comprising formula 1 and theirpharmaceutically acceptable salts.

The term “osteoporosis” as used herein means the state that minerals andsubstrates are reduced abnormally in large amounts, so that there is nodefect in their structure, however, o many pores develop in the bone,making it like sponge and more likely to fracture. In specific examples,the benzamidine compounds of the present invention suppressed thedifferentiation of osteoclast, facilitated bone formation, andremarkably inhibited the bone mass reduction in osteoporosis-inducedanimal models.

The term “bone fracture” as used herein means one of various physicalinjuries of a bone, based on a complete or incomplete disruption of thecontinuity of a bone, which are classified according to anatomicallocation (epiphyseal, metaphyseal, diaphyseal, intra-articular,proximal, midshaft, distal, etc.), degree of fracture (complete,incomplete), direction of fracture (transverse, oblique, spiral,longitudinal), presence of open wound (open, closed), number offractures (simple, linear, segmental, comminuted, etc.), stability offracture (stable, unstable), displacement of fracture, etc. As comparedto a non-treated group, a group treated with the benzamidine compound ofthe formula 1 according to the present invention was found to have bonycallus which significantly decreased in volume in a dose-dependentpattern, but increased both in bone density and in bone strength, withsignificance, in a dose-dependent pattern.

The term “allergic inflammatory diseases” means non-specificinflammatory diseases caused by various allergens, exemplified byallergic rhinitis, asthma, allergic conjunctivitis, allergic dermatitis,atopic dermatitis, contact dermatitis, urticaria, etc. In the specificembodiment of the present invention, the benzamidine compound of theformula 1 was found to have a great effect of reducing lung weight andtotal leukocyte numbers in asthma-induced animal models.

The composition of the present invention, a composition may comprisesmedicinally effective ingredient equivalents or similar in function tothe benzamidine compound of Chemical Formula 1 or its pharmaceuticallyacceptable salt, in addition to Chemical Formula 1 or itspharmaceutically acceptable salt.

The composition of the present invention may comprise one or morepharmaceutically acceptable carriers. A proper carrier may be selectedfrom a group consisting of saline, sterilized water, Ringer's solution,buffered saline, a dextrose solution, a maltodextrin solution, glycerol,ethanol, and combinations thereof, and may be, if necessary, furthersupplemented with other typical additives such as an antioxidant, abuffer, a static agent, etc. In combination with a diluent, adispersant, a surfactant, a binder, and a lubricant, the composition ofthe present invention may also be formulated into injectable dosageforms, such as aqueous solutions, suspensions, emulsions, etc., pills,capsules, granules, and tablets. Moreover, depending on the kind ofingredient or disease, the formulation may be produced using methodsknown in the art or disclosed in Remington's Pharmaceutical Science((latest version), Mack Publishing Company, Easton Pa.).

The composition of the present invention may be administered orally orparenterally (e.g., intravenously, subcutaneously, intraabdominally, ortopically). The dosage of the composition of the present inventionvaries depending on body weight, age, gender, health state, diet,administration time period, administration route, excretion rate,disease severity, etc. When all of these factors are taken into account,the benzamidine compound of Chemical Formula 1 is administered once ormany times at a dose of approximately 10 to 1,000 mg/kg a day, andpreferably at a dose of approximately 50 to 500 mg/kg a day.

For the prevention and treatment of osteoporosis, allergic inflammatorydisease and physical injury of bone comprising fracture, theadministration of the composition of the present invention can be donealone or in combination with surgery, hormone therapy, chemical therapy,and/or a biological response controller.

A better understanding of the present invention may be obtained throughthe following examples which are set forth to illustrate, but are not tobe construed as the limit of the present invention.

Preparative Example 1 Preparation of Compound (12) in Reaction Scheme 11-1: 4-(5-chloropentoxyl)-benzonitrile (4)

While 3.0 g (25.2 mmol) of 4-hydroxybenzonitrile were added to 80 ml ofacetonitrile and stirred, 3.67 g (27 mmol) of potassium carbonate and4.67 g (25.2 mmol) of 1-bromo-5-chloropentane were added. Subsequently,the temperature was gradually increased and stirring under reflux wascontinued for 7 hr, and then stirring was further continued to 80-82° C.The temperature was decreased to room temperature, and Ethyl acetate wasadded, and organic layer washed with distilled water. Thereafter, theorganic layer was dried over anhydrous magnesium sulfate, and thenconcentrated under reduced pressure. The concentrated compound wasrecrystallized in methanol, then filtered, and washed with −10° C.methanol, thus obtaining 5.09 g (yield: 90.3%) of a title compound (4).

m.p. 47˜49° C.;

¹H-NMR (CDCl₃) (ppm) 1.64 (m, 2H), 1.82 (m, 4H), 3.57 (t, 2H), 4.01 (t,2H), 6.93 (d, 2H), 7.57 (d, 2H)

1-2: 1-(4-methoxyphenyl)-1-propanone (7)

While 49.3 g (370 mmol) of aluminium chloride were added to 200 ml ofdichloromethane and stirred, 40 g (370 mmol) of anisole were slowlyadded in droplets at 5° C. Subsequently, 32 ml (370 mmol) of propionylchloride were slowly added in droplets for 30 min, and stirring wasfurther continued at room temperature for 2 hr. After the reaction wascompleted, the resultant reaction mixture was diluted withdichloromethane, and then washed with a saturated aqueous solution ofsodium bicarbonate and water at 5° C. The organic layer was dried overanhydrous magnesium sulfate and then concentrated under reducedpressure. Organic residue was purified with column-chromatography inwhich the mixture of ethyl acetate and n-hexane (1:10) were used as aeluent, thus obtaining 59.5 g (yield: 98%) of a title compounnd (7).

¹H-NMR (DMSO-d₆) (ppm) 1.05 (t, 3H), 2.94 (q, 2H), 3.81 (s, 3H), 7.02(d, 2H), 7.93 (d, 2H)

1-3: 1-(4-hydroxyphenyl)propan-1-one (8)

While 20 g (0.121 mmol) of 1-(4-methoxyphenyl)-1-propanone (7) preparedin Example 1-2 were added to 139 ml (2.4 mol) of acetic acid andstirred, 270 ml (2.4 mmol) of 48% bromic acid were added. Subsequently,the temperature was gradually increased to 100° C. and stirring underreflux was continued for 18 hr. The temperature was decreased to roomtemperature, and ethyl acetate was added, and organic layer was washedwith water. Thereafter, the organic layer was washed with a saturatedaqueous solution of potassium carbonate, then concentrated under reducedpressure, after which the precipitated solid was recrystallized withethyl acetate/n-hexane system, and filtered, thus obtaining 12.7 g(yield: 70%) of a title compound (8) as a solid.

m.p.: 143˜150° C.

¹H-NMR (DMSO-d₆) (ppm) 1.03 (t, 3H), 2.91 (q, 2H), 6.83 (d, 2H), 7.82(d, 2H), 10.28 (s, 1H).

1-4: 4-[5-(4-propionylphenoxy)pentoxyl]-benzonitrile (9)

While 12 g (80 mmol) of 1-(4-hydroxyphenyl)propan-1-one (8) prepared inExample 1-3 were added to 100 ml of dimethylformamide and stirred, 3.5 g(84 mmol) of sodium hydride were added, and stirring was continued for20 min. Thereafter, 17.9 g (80 mmol) of4-(5-chloro-pentoxy)-benzonitrile (4) prepared in Example 1-1 weredissolved in 20 ml of dimethylformamide. The reaction temperature wasgradually increased and stirring was continued at 40° C. for 4 hr. Afterthe reaction was completed, the temperature was decreased to roomtemperature, and the resultant reaction mixture was added withethylacetate, and then washed with distilled water. Subsequently, theorganic layer was dried over anhydrous magnesium sulfate, and thenconcentrated under reduced pressure. The residue was purified withcolumn-chromatography in which the mixture of ethylacetate and n-hexane(1:5) were used as a eluent, thus obtaining 21.6 g (yield: 80%) of atitle compound (9).

m.p.: 107˜111° C.

¹H-NMR (DMSO-d₆) (ppm) 1.04 (t, 3H), 1.56 (m, 2H), 1.78 (brm, 4H), 2.95(q, 2H), 4.07 (4H), 7.00 (d, 2H), 7.08 (d, 2H), 7.74 (d, 2H), 7.90 (d,2H).

1-5: 4-5-[4-(2-bromopropionyl)phenoxy]pentoxy-benzonitrile (10)

While 20 g (59 mmol) of 4-[5-(4-propionylphenoxy)pentoxy]-benzonitrile(9) prepared in Example 1-4 were added to 300 ml of ethylacetate andstirred, 26 g (119 mmol) of copper(II) bromide were added, and thereaction temperature was gradually increased and stirring was continuedat 70° C. for 8 hr. After the reaction was completed, the resultantreaction mixture was cooled to room temperature and the salts wereremoved by filtration. The ethylacetate layer was washed with sodiumbicarbonate and sodium chloride. Subsequently, the organic layer wasdried over anhydrous magnesium sulfate and then concentrated underreduced pressure, thus obtaining 23 g (yield: 95.0%) of a title compound(10).

m.p.: 79˜81° C.

¹H-NMR (DMSO-d₆) (ppm) 1.57 (m, 2H), 1.74 (d, 2H), 1.79 (brm, 4H), 4.08(m, 4H), 5.77 (q, 1H), 7.07 (m, 4H), 7.74 (d, 2H), 7.99 (d, 2H).

1-6:4-5-[4-(5-methyl-2-isopropyl-1,3-thiazol-4-yl)phenoxy]pentoxyl-benzonitrile(12)

While 1 g (2.4 mmol) of4-5-[4-(2-bromopropionyl)phenoxy]pentoxyl-benzonitrile (10) prepared inExample 1-5 were added to 30 ml of ethanol and stirred, 0.25 g (2.4mmol) of isobutrathioamide were added. Subsequently, the temperature wasgradually increased to 80° C. and stirring under reflux was continuedfor 5 hr. After the reaction was completed, the resultant reactionmixture was concentrated under reduced pressure, and diluted withdichloromethane, and then washed with a saturated aqueous solution ofsodium bicarbonate and brine. The organic layer was dried over anhydrousmagnesium sulfate, and then concentrated under reduced pressure. Theresidue was purified with column-chromatography in which the mixture ofethylacetate and n-hexane (1:6) were used as a eluent, thus obtaining0.9 g (yield: 89%) of a title compound (12).

m.p.: 70˜73° C.

¹H-NMR (DMSO-d₆) (ppm) 1.32 (d, 6H), 1.59 (m, 2H), 1.79 (m, 4H), 2.47(s, 3H), 3.21 (m, 1H), 4.02 (t, 2H), 4.09 (t, 2H), 6.98 (d, 2H), 7.09(d, 2H), 7.55 (d, 2H), 7.74 (d, 2H).

Preparative Example 2 Preparation of Compound (16) in Reaction Scheme 22-1:4-5-[4-(5-methyl-2-amino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzonitrile(14)

While 3 g (7.2 mmol) of4-5-[4-(2-bromopropionyl)phenoxy]pentoxyl-benzonitrile (10) prepared inExample 1-5 were added to 30 ml of ethanol and stirred, 0.58 g (7.6mmol) of thiourea were added. Subsequently, the temperature wasgradually increased to 80° C. and stirring under reflux was continuedfor 5 hr. After the reaction was completed, the resultant reactionmixture was concentrated under reduced pressure, and diluted withdichloromethane, and then washed with a saturated aqueous solution ofsodium bicarbonate and brine. The organic layer was dried over anhydrousmagnesium sulfate, and then concentrated under reduced pressure. Theresidue was purified with column-chromatography in which the mixture ofethylacetate and hexane (1:2) were used as a eluent, thus obtaining 2.5g (yield: 89%) of a title compound (14).

¹H-NMR (DMSO-d₆) (ppm) 1.57 (m, 2H), 1.78 (m, 4H), 2.27 (s, 3H), 3.98(t, 2H), 4.07 (t, 2H), 6.69 (s, 2H), 6.91 (d, 2H), 7.09 (d, 2H), 7.45(d, 2H), 7.74 (d, 2H).

2-2:4-5-[4-(5-methyl-2-ethylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzonitrile(16)

While 0.60 g (1.52 mmol) of4-5-[4-(5-methyl-2-amino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzonitrile(14) prepared in Example 2-1 were added to 50 ml of dimethylformamideand stirred, 0.07 g (1.83 mmol) of sodium hydride were added. Afterstirring for 20 min, 0.13 ml (1.6 mmol) of ethyl iodide were added, andthe temperature was gradually increased to 40° C. and stirring wascontinued for 4 hr. After the reaction was completed, the resultantreaction mixture was partitioned between distilled water andethylacetate. The organic layer was dried over anhydrous magnesiumsulfate, and then concentrated under reduced pressure. The residue waspurified with column-chromatography in which the mixture of ethylacetateand n-hexane (1:2) were used as a eluent, thus obtaining 0.32 g (yield:50%) of a title compound (16).

¹H-NMR (DMSO-d₆ (ppm) 1.13 (t, 3H), 1.56 (m, 2H), 1.78 (m, 4H), 2.28 (s,3H), 3.19 (m, 2H), 3.99 (t, 2H), 4.07 (t, 2H), 6.92 (d, 2H), 7.09 (d,2H), 7.26 (t, 1H), 7.47 (d, 2H), 7.74 (d, 2H).

Preparative Example 3 Preparation of Compound (18) in Reaction Scheme 34-5-[4-(5-methyl-2-[ethyl-(2-morpholinoethyl)amino]-1,3-thiazol-4-yl)phenoxy]pentoxy-benzonitrile(18)

While 0.40 g (0.94 mmol) of4-5-[4-(5-methyl-2-ethylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzonitrile(16) prepared in Example 2-2 were added to 50 ml of dimethylsulfoxideand stirred, 0.10 g (2.37 mmol) of sodium hydride were added. Afterstirring for 20 min, 0.18 g (0.99 mmol) of N-(2-chloroethyl)morpholinehydrochloride were added, and the temperature was gradually increased to40° C. and stirring was continued for 4 hr. After the reaction wascompleted, the resultant reaction mixture was partitioned betweendistilled water and ethylacetate. The organic layer was dried overanhydrous magnesium sulfate, and then concentrated under reducedpressure. The residue was purified with column-chromatography in whichthe mixture of ethylacetate and n-hexane (1:2) were used as a eluent,thus obtaining 0.35 g (yield: 70%) of a title compound (18).

¹H-NMR (DMSO-d₆) (ppm) 1.15 (t, 3H), 1.55 (m, 2H), 1.77 (brm, 4H), 2.31(s, 3H), 2.42 (brm, 4H), 2.51 (m, 2H), 3.39 (t, 2H), 4.07 (t, 2H), 6.93(d, 2H), 7.09 (d, 2H), 7.48 (d, 2H), 7.74 (d, 2H).

Preparative Example 4 Preparation of Compound (20) in Reaction Scheme 44-5-[4-(5-methyl-2-piperidino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzonitrile(20)

While 0.50 g (1.27 mmol) of4-5-[4-(5-methyl-2-amino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzonitrile(14) prepared in Example 2-1 were added to 50 ml of dimethylformamideand stirred, 0.11 g (2.79 mmol) of sodium hydride were added. Afterstirring for 20 min, 0.19 ml (1.4 mmol) of 1,5-dibromopentane was added,and the temperature was gradually increased to 40° C. and stirring wascontinued for 4 hr. After the reaction was completed, the resultantreaction mixture was partitioned between distilled water andethylacetate. The organic layer was dried over anhydrous magnesiumsulfate, and then concentrated under reduced pressure. The residue waspurified with column-chromatography in which the mixture of ethylacetateand n-hexane (1:2) were used as a eluent, thus obtaining 0.57 g (yield:98%) of a title compound (20).

¹H-NMR (DMSO-d₆) (ppm) 1.57 (m, 2H), 1.63 (brm, 6H), 1.77 (brm, 4H),2.20 (s, 3H), 3.60 (brm, 4H), 4.04 (m, 4H), 7.04 (d, 4H), 7.40 (d, 2H),7.68 (d, 2H).

Example 1 Preparation ofN-hydroxy-4-5-[4-(5-methyl-2-isopropyl-1,3-thiazol-4-yl)phenoxy]pentoxyl-benzamidine

While 0.3 g (0.71 mmol) of4-5-[4-(5-methyl-2-isopropyl-1,3-thiazol-4-yl)phenoxy]pentoxyl-benzonitrile(12) prepared in Example 1-6 were added to 10 ml of ethanol and stirred,0.11 g (2.9 mmol) of sodium hydroxide and 0.20 g (2.9 mmol) ofhydrochloride, dissolved in ethanol (5 ml)/water (1 ml) co-solvent, wereadded. The temperature was gradually increased to 80° C. and stirringwas continued for 15 hr. The resultant reaction mixture was concentratedunder reduced pressure, and diluted with dichloromethane, and thenwashed with a distilled water. The organic layer was dried overanhydrous magnesium sulfate and then the resultant reaction mixture wasconcentrated under reduced pressure, then purified withcolumn-chromatography in which the mixture of ethylacetate, n-hexane andmethanol (5:10:1) were used as a eluent, thus obtaining 0.19 g (yield:52%) of a title compound.

¹H-NMR (DMSO-d₆) (ppm) 1.31 (d, 6H), 1.58 (m, 2H), 1.79 (m, 4H), 2.47(s, 3H), 3.21 (m, 1H), 4.00 (m, 4H), 5.71 (s, 2H), 6.91 (d, 2H), 6.99(d, 2H), 7.56 (m, 4H), 9.44 (s, 1H).

Example 2 Preparation of4-5-[4-(5-methyl-2-isopropyl-1,3-thiazol-4-yl)phenoxy]pentoxyl-benzamidine

While 0.22 g (0.52 mmol) of4-5-[4-(5-methyl-2-isopropyl-1,3-thiazol-4-yl)phenoxy]pentoxyl-benzonitrile(12) prepared in Example 1-6 were added to 10 ml of saturatedhydrochloride/methanol solution and stirred for 24 hr, and the resultantreaction mixture was concentrated under reduced pressure. The organicresidue was dissolved with 2 ml of ethanol, and put it in sealed tube.10 ml of ammonia ethanol solution was added to the tube, and thetemperature was gradually increased to 50° C. and stirring was continuedfor 40 hr. After the reaction was completed, the resultant reactionmixture was concentrated under reduced pressure, and was purified withcolumn-chromatography in which the mixture of chloroform, methanol (8:1)were used as chromatography solvent, thus obtaining 0.10 g (yield: 48%)of a title compound.

¹H-NMR (DMSO-d₆) (ppm) 1.33 (d, 6H), 1.61 (m, 2H), 1.82 (brm, 4H), 2.49(s, 3H), 3.22 (m, 1H), 4.04 (t, 2H), 4.14 (t, 2H), 7.01 (d, 2H), 7.17(d, 2H), 7.57 (d, 2H), 7.85 (d, 2H).

Examples 3 to 83 1. N-hydroxy benzamidine (R₅=OH) Examples 3 to 51, 57to 83

Compound (12) prepared according to the same method as that in thePreparative Example 1-6 was reacted in the same manner as Example 1,obtaining the title compounds shown I Table 1.

Table 1 shows the title compounds, reactants and ¹H-NMR data.

TABLE 1 Acid example name chloride Thioamide Alkylhalide 1N-hydroxy-4-5-[4- Propionylchloride Thioisobutramide (2-isopropyl-5-methyl-1,3- thiazol-4- yl)phenoxy]pentoxy- benzamidine 2 4-5-[4-(2-Propionylchloride Thioisobutramide isopropyl-5- methyl-1,3- thiazol-4-yl)phenoxy]pentoxy- benzamidine 3 N-hydroxy-4-5-[4- AcetylchlorideThioacetamide (2-methyl-1,3- thiazol-4- yl)phenoxy]pentoxy- benzamidine4 N-hydroxy-4-5-[4- Acetylchloride Thiopropionamide (2-ethyl-1,3-thiazol-4- yl)phenoxy]pentoxy- benzamidine 5 N-hydroxy-4-5-[4-Acetylchloride Thioisobutramide (2-isopropyl-1,3- thiazol-4-yl)phenoxy]pentoxy- benzamidine 6 N-hydroxy-4-5-[4- AcetylchlorideThiobenzamide (2-phenyl-1,3- thiazol-4- yl)phenoxy]pentoxy- bEnzamidine7 N-hydroxy-4-5-[4- Acetylchloride Thionicotinamide (2-pyridin-3-yl-1,3-thiazol-4- yl)phenoxy]pentoxy- benzamidine 8 N-hydroxy-4-5-[4-Acetylchloride Cyclohexanecarbothioic (2-cyclohexyl-1,3- acide amidethiazol-4- yl)phenoxy]pentoxy- benzamidine 9 N-hydroxy-4-5-[4-Acetylchloride Thiohexanoamide (2-pentyl-1,3- thiazol-4-yl)phenoxy]pentoxy- benzamidine 10 N-hydroxy-4-5-[4- PropionylchlorideThioacetamide (2,5-dimethyl-1,3- thiazol-4- yl)phenoxy]pentoxy-benzamidine 11 N-hydroxy-4-5-[4- Propionylchloride Thiopropionamide(2-ethyl-5-methyl- 1,3-thiazol-4- yl)phenoxy]pentoxy- benzamidine 12N-hydroxy-4-5-[4- Propionylchloride Thiobenzamide (5-methyl-2-phenyl-1,3- thiazol-4- yl)phenoxy]pentoxy- benzamidine 13N-hydroxy-4-5-[4- Propionylchloride Thionicotinamide (5-methyl-2-pyridin-3-yl-1,3- thiazol-4- yl)phenoxy]pentoxy- benzamidine 14N-hydroxy-4-5-[4- Propionylchloride Cyclohexanecarbothioic(2-cyclohexyl-5- acide methyl-1,3- amide thiazol-4- yl)phenoxy]pentoxy-benzamidine 15 N-hydroxy-4-5-[4- Propionylchloride Thiohexanoamide(5-methyl-2- pentyl-1,3- thiazol-4- yl)phenoxy]pentoxy- benzamidine 16N-hydroxy-4-5-[4- Propionylchloride 2,2- (2-t-butyl-5-dimethylthiopropionamide methyl-1,3- thiazol-4- yl)phenoxy]pentoxy-benzamidine 17 N-hydroxy-4-5-[4-(5- Butrylchloride Thioacetamideethyl-2-methyl-1,3- thiazol-4- yl)phenoxy]pentoxy- benzamidine 18N-hydroxy-4-5-[4- Butrylchloride Thiopropionamide (2,5-diethyl-1,3-thiazol-4- yl)phenoxy]pentoxy- benzamidine 19 N-hydroxy-4-5-[4-(5-Butrylchloride Thioisobutramide ethyl-2-isopropyl- 1,3-thiazol-4-yl)phenoxy]pentoxy- benzamidine 20 N-hydroxy-4-5-[4-(5- ButrylchlorideThiobenzamide ethyl-2-phenyl-1,3- thiazol-4- yl)phenoxy]pentoxy-benzamidine 21 N-hydroxy-4-5-[4-(5- Butrylchloride Thionicotinamideethyl-2-pyridin-3-yl- 1,3-thiazol-4- yl)phenoxy]pentoxy- benzamidine 22N-hydroxy-4-5-[4-(2- Butrylchloride Cyclohexanecarbothioiccyclohexyl-5-ethyl- acide 1,3-thiazol-4- amide yl)phenoxy]pentoxy-benzamidine 23 N-hydroxy-4-5-[4-(5- Butrylchloride Thiohexanoamideethyl-2-pentyl-1,3- thiazol-4- yl)phenoxy]pentoxy- benzamidine 24N-hydroxy-4-5-[4-(2- Isovalerylchloride Thiopropionamideethyl-5-isopropyl- 1,3-thiazol-4- yl)phenoxy]pentoxy- benzamidine 25N-hydroxy-4-5-[4- Isovalerylchloride Thioisobutramide (2,5-diisopropyl-1,3-thiazol-4- yl)phenoxy]pentoxy- benzamidine 26 N-hydroxy-4-5-[4-Isovalerylchloride Thiobenzamide (5-isopropyl-2- phenyl-1,3- thiazol-4-yl)phenoxy]pentoxy- benzamidine 27 N-hydroxy-4-5-[4- IsovalerylchlorideThionicotinamide (5-isopropyl-2- pyridin-3-yl-1,3- thiazol-4-yl)phenoxy]pentoxy- benzamidine, 28 N-hydroxy-4-5-[4- IsovalerylchlorideThiohexanoamide (5-isopropyl-2- pentyl-1,3- thiazol-4-yl)phenoxy]pentoxy- benzamidine 29 N-hydroxy-4-5-[4- PentanoylThioacetamide (2-methyl-5- chloride propyl-1,3- thiazol-4-yl)phenoxy]pentoxy- benzamidine 30 N-hydroxy-4-5-[4- HexanoylchlorideThioacetamide (5-butyl-2-methyl- 1,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine 31 N-hydroxy-4-5-[4- Hexanoylchloride Thiopropionamide(5-butyl-2-ethyl- 1,3-thiazol-4- yl)phenoxy]pentoxy- benzamidine 32N-hydroxy-4-5-[4- Hexanoylchloride Thioisobutramide (5-butyl-2-isopropyl-1,3- thiazol-4- yl)phenoxy]pentoxy- benzamidine 33N-hydroxy-4-5-[4- Hexanoylchloride Thiobenzamide (5-butyl-2-phenyl-1,3-thiazol-4- yl)phenoxy]pentoxy- benzamidine 34 N-hydroxy-4-5-[4-Hexanoylchloride Thionicotinamide (5-butyl-2- pyridin-3-yl-1,3-thiazol-4- yl)phenoxy]pentoxy- benzamidine 35 N-hydroxy-4-5-[4-Hexanoylchloride Cyclohexanecarbothioic (5-butyl-2- acid amidecyclohexyl-1,3- thiazol-4- yl)phenoxy]pentoxy- benzamidine 36N-hydroxy-4-5-[4- Hexanoylchloride Thiohexanoamide (5-butyl-2-pentyl-1,3-thiazol-4- yl)phenoxy]pentoxy- benzamidine 37 N-hydroxy-4-5-[4-Hexanoylchloride 2,2- (5-butyl-2-t- dimethylthiopropionamidebutyl-1,3-thiazol- 4- yl)phenoxy]pentoxy- benzamidine 38N-hydroxy-4-5-[4- Hydrocinnamoyl Thioaectamide (5-benzyl-2- chloridemethyl-1,3- thiazol-4- yl)phenoxy]pentoxy- benzamidine 39N-hydroxy-4-5-[4- Hydrocinnamoyl Thioisobutramide (5-benzyl-2- chlorideisopropyl-1,3- thiazol-4- yl)phenoxy]pentoxy- benzamidine 40N-hydroxy-4-5-[4- Hydrocinnamoyl Thiobenzamide (5-benzyl-2- chloridephenyl-1,3- thiazol-4- yl)phenoxy]pentoxy- benzamidine 41N-hydroxy-4-5-[4- hydrocinnamoyl thionicotinamide (5-benzyl-2- chloridepyridin-3-yl-1,3- thiazol-4- yl)phenoxy]pentoxy- benzamidine 42N-hydroxy-4-(5-[4- 4- thioacetamide (5-(2-chloro- chlorobutyrylchlorideethyl)-2-methyl- 1,3-thiazol-4- yl]phenoxy)pentoxy)- benzamidine 43N-hydroxy-4-(5-[4- cyclopentyl thioacetamide (5-cyclopentyl-acetylchloride 2methyl-1,3- thiazol-4- yl)phenoxy]pentoxy)- benzamidine44 N-hydroxy-4-(5-[4- isocaproic thioacetamide (5-isobutyl-2- chloridemethyl-1,3- thiazol-4- yl)phenoxy]pentoxy)- benzamidine 45N-hydroxy-4-5-[4- cyclopentylpropionylchloride thioacetamide (5-cyclopentylmethyl- 2-methyl-1,3- thiazol-4- yl)phenoxy]pentoxy-benzamidine 46 N-hydroxy-4-5-[4- cyclopentylpropionylchloridethiopropionamide (5- cyclopentylmethyl- 2-ethyl-1,3- thiazol-4-yl)phenoxy]pentoxy- benzamidine 47 N-hydroxy-4-5-[4-cyclopentylpropionylchloride thioisobutramide (5- cyclopentylmethyl-2-isopropyl-1,3- thiazol-4- yl)phenoxy]pentoxy- benzamidine 48N-hydroxy-4-5-[4- cyclopentylpropionylchloride thiobenzamide (5-cyclopentylmethyl- 2-phenyl-1,3- thiazol-4- yl)phenoxy]pentoxy-benzamidine 49 N-hydroxy-4-5-[4- cyclopentylpropionylchloridethionicotinamide (5- cyclopentylmethyl- 2-pyridin-3-yl- 1,3-thiazol-4-yl)phenoxy]pentoxy- benzamidine 50 N-hydroxy-4-5-[4-cyclopentylpropionylchloride Cyclohexanecarbothioic (5- acidcyclopentylmethyl- amide 2-cyclohexyl-1,3- thiazol-4-yl)phenoxy]pentoxy- benzamidine 51 N-hydroxy-4-5-[4-cyclopentylpropionylchloride thiohexanoamide (5- cyclopentylmethyl-2-pentyl-1,3- thiazol-4- yl)phenoxy]pentoxy- benzamidine 57N-hydroxy-4-5-[4- acetylchloride thiourea (2-amino-1,3- thiazol-4-yl)phenoxy]pentoxy- benzamidine 58 N-hydroxy-4-5-[4- propionylchloridethiourea (2-amino-5-methyl- 1,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine 59 N-hydroxy-4-5-[4- propionylchloride amidino(2-guanidino-5- thiourea methyl-1,3- thiazol-4- yl)phenoxy]pentoxy-benzamidine 60 N-hydroxy-4-5-[4- butrylchloride thiourea(2-amino-5-ethyl- 1,3-thiazol-4- yl)phenoxy]pentoxy- benzamidine 61N-hydroxy-4-5-[4- isovalerylchloride thiourea (2-amino-5- isopropyl-1,3-thiazol-4- yl)phenoxy]pentoxy- benzamidine 62 N-hydroxy-4-5-[4-isovalerylchloride amidino (2-guanidino-5- thiourea isopropyl-1,3-thiazol-4- yl)phenoxy]pentoxy- benzamidine 63 N-hydroxy-4-5-[4-hexanoylchloride thiourea (2-amino-5-butyl- 1,3-thiazol-4-yl)phenoxy]pentoxy- benzamidine 64 N-hydroxy-4-5-[4- hexanoylchlorideamidino (5-butyl-2- thiourea guanidino-1,3- thiazol-4-yl)phenoxy]pentoxy- benzamidine 65 N-hydroxy-4-5-[4- hydrocinnamoylthiourea (2-amino-5-benzyl- chloride 1,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine 66 N-hydroxy-4-5-[4- hydrocinnamoyl amidino (5-benzyl-2-chloride thiourea guanidino-1,3- thiazol-4- yl)phenoxy]pentoxy-benzamidine 67 N-hydroxy-4-5-[4- cyclopentylpropionylchloride thiourea(2-amino-5- cyclopentylmethyl- 1,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine 68 N-hydroxy-4-5-[4- cyclopentylpropionylchloride piperidin-propylbromide (5- 4- cyclopentylmethyl- carbothioic 2-(1-propyl- acidpiperidin-4$$)-1,3- amide thiazol-4- yl)phenoxy]pentoxy- benzamidine 69N-[4-(4-(5-[4-(N- propionylchloride N- hydroxy 2(amino- carbamimidoyl-2- phenoxy)pentoxy]- thioxoethyl)- phenyl]-5-methyl- 2- thiazol-2-methyl ylmethyl)- propanamide isobutylamide 70 N-hydroxy-4-5-[4-(5-isovalerylchloride glycine bis- isopropyl-2- thioamide (dibromide)-morpholinomethyl- ethylester 1,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine 71 N-hydroxy-4-5-[4-(2- hydrocinnamoly glycineaminomethyl-5- chloride thioamide benzyl-1,3-thiazol- 4-yl)phenoxy]pentoxy- benzamidine 72 N-hydroxy-4-5-[4-(5-propionylchloride piperidin- propylbromide methyl-2-(1-propyl- 4-piperidin-4yl)-1,3- carbothioic thiazol-4- acid yl)phenoxy]pentoxy-amide benzamidine 73 N-hydroxy-4-5-[4-(5- isovalerylchloride 2-amino-isopropyl-2- thioacetamide aminomethyl-1,3- thiazol-4-yl)phenoxy]pentoxy- benzamidine 74 N-hydroxy-4-5-[4-(5- 4- thioacetamidevinyl-2-methyl-1,3- chlorobutryl thiazol-4- chloride yl)phenoxy]pentoxy-benzamidine 75 N-hydroxy-4-5-[4-(5- methoxyacetyl thioacetamidehydroxymethyl-2- chloride methyl-1,3-thiazol- 4- yl)phenoxy]pentoxy-benzamidine 76 N-hydroxy-4-5-[4-(5- methoxyacetyl thioacetamidemethoxymethyl-2- chloride methyl-1,3-thiazol- 4- yl)phenoxy]pentoxy-benzamidine 77 N-hydroxy-4-5-[4-(5- 4- thiourea (2-chloroethyl)-2-chlorobutryl amino-1,3-thiazol-4- chloride yl)phenoxy]pentoxy-benzamidine 78 N-hydroxy-4-5-[4-(5- 4- thiourea vinyl-2-amino-1,3-chlorobutryl thiazol-4- chloride yl)phenoxy]pentoxy- benzamidine 79N-hydroxy-4-5-[4-(5- 4- thionicotinamide vinyl-2-(pyridin-3-chlorobutryl yl)-1,3-thiazol-4- chloride yl)phenoxy]pentoxy- benzamidine80 N-hydroxy-4-5-[4- 4- thionicotinamide (5-(2- chlorobutrylchloroethyl)-2- chloride (pyridin-3-yl)- 1,3-thiazol-4-yl)phenoxy]pentoxy- benzamidine 81 N-hydroxy-4-5-[4- cyclopentylacetylthiourea (2-amino-5- chloride cyclopentyl-1,3- thiazol-4-yl)phenoxy]pentoxy- benzamidine 82 N-hydroxy-4-5-[4- butrylchloride2-amino- (5-ethyl-2- thioacetamide aminomethyl-1,3- thiazol-4-yl)phenoxy]pentoxy- benzamidine 83 N-hydroxy-4-5-[4- isovalerylchloridepiperidin- (5-isopropyl-2- 3- (piperidin-3-yl)- carbothioic1,3-thiazol-4- acid amide yl)phenoxy]pentoxy- benzamidine example NMRsolvent mp  1 1.31 (d, 6H), 1.58 (m, 2H), DMSO-d₆ — 1.79 (m, 4H), 2.47(s, 3H), 3.21 (m, 1H), 4.00 (m, 4H), 5.71 (s, 2H), 6.91 (d, 2H), 6.99(d, 2H), 7.56 (m, 4H), 9.44 (s, 1H)  2 1.33 (d, 6H), 1.61 (m, 2H),DMSO-d₆ — 1.82 (brm, 4H), 2.49 (s, 3H), 3.22 (m, 1H), 4.04 (t, 2H), 4.14(t, 2H), 7.01 (d, 2H), 7.17 (d, 2H), 7.57 (d, 2H), 7.85 (d, 2H).  3 1.56(m, 2H), 1.78 (brm, DMSO-d₆ 139-140 4H), 2.68 (s, 3H), 4.00 (m, 4H),5.70 (s, 2H), 6.90 (d, 2H), 6.96 (d, 2H), 7.57 (d, 2H), 7.72 (s, 1H),7.83 (d, 2H), 9.43 (s, 1H)  4 1.32 (t, 3H), 1.57 (brm, DMSO-d₆ 2H), 1.77(brm, 4H), 3.01 (q, 2H), 4.00 (m, 4H), 5.71 (s, 2H), 6.91 (d, 2H), 6.96(d, 2H), 7.57 (d, 2H), 7.75 (s, 1H), 7.84 (d, 2H), 9.43 (s, 1H)  5 1.35(d, 6H), 1.58 (m, 2H), DMSO-d₆ 95-129 1.78 (brm, 4H), 3.28 (m, 1H), 4.00(m, 4H), 5.79 (brs, 2H), 6.91 (d, 2H), 6.97 (d, 2H), 7.58 (d, 2H), 7.76(s, 1H), 7.84 (d, 2H), 9.47 (s, 1H)  6 1.58 (m, 2H), 1.80 (brm, DMSO-d₆133-141 4H), 4.02 (m, 4H), 5.81 (brs, 2H), 6.92 (d, 2H), 7.01 (d, 2H),7.51 (m, 3H), 7.58 (d, 2H), 7.96 (d, 2H), 8.01 (m, 3H), 9.49 (s, 1H)  71.58 (brm 2H), 1.80 (brm, DMSO-d₆ 149-154 4H), 4.02 (t, 4H), 5.73 (s,2H), 6.91 (d, 2H), 7.02 (d, 2H), 7.55 (m, 3H), 7.82 (d, 2H), 7.97 (d,2H), 8.10 (s, 1H), 8.36 (d, 1H), 8.67 (d, 1H), 9.19 (s, 1H), 9.45 (s,1H)  8 1.23 (m, 1H), 1.47 (m, 6H), DMSO-d₆ 1.65 (m, 1H), 1.77 (brm, 6H),2.06 (m, 2H), 2.99 (m, 1H), 4.00 (m, 4H), 5.70 (s, 2H), 6.90 (d, 2H),6.96 (d, 2H), 7.57 (d, 2H), 7.74 (d, 2H), 7.83 (d, 2H), 9.44 (s, 1H)  90.86 (t, 3H), 1.33 (brm, 4H), DMSO-d₆ 1.56 (brm, 2H), 1.73 (brm, 6H),2.97 (m, 2H), 4.00 (m, 4H), 5.70 (s, 2H), 6.90 (d, 2H), 6.96 (m, 2H),7.57 (d, 2H), 7.74 (s, 1H), 7.83 (d, 2H), 9.44 (s, 1H) 10 1.57 (m, 2H),1.78 (m, 4H), DMSO-d₆ 128-133 2.44 (s, 3H), 2.58 (s, 3H), 4.01 (m, 4H),5.72 (s, 2H), 6.97 (d, 2H), 7.54 (d, 2H), 7.57 (d, 2H), 9.44 (s, 1H) 111.27 (t, 3H), 1.57 (m, 2H), DMSO-d₆ 127-131 1.78 (brm, 4H), 2.45 (s,3H), 2.91 (q, 2H), 4.01 (m, 4H), 5.75 (brs, 2H), 6.91 (d, 2H), 6.98 (d,2H), 7.54 (d, 2H), 7.57 (d, 2H), 9.46 (s, 1H). 12 1.58 (m, 2H), 1.79 (m,4H), DMSO-d₆ 124-130 2.56 (s, 3H), 4.02 (m, 4H), 5.78 (brs, 2H), 6.91(d, 2H), 7.03 (d, 2H). 7.49 (m, 3H), 7.58 (d, 2H), 7.65 (d, 2H), 7.91(d, 2H), 9.45 (s, 1H) 13 1.59 (m, 2H), 1.79 (m, 2H), DMSO-d₆ 138-1502.58 (s, 3H), 4.02 (m, 4H), 5.72 (s, 2H), 6.91 (d, 2H), 7.03 (d, 2H),7.52 (m, 1H), 7.58 (d, 2H), 7.66 (d, 2H), 8.26 (d, 1H), 8.64 (d, 1H),9.09 (d, 1H), 9.45 (s, 1H) 14 1.26 (m, 1H), 1.43 (brm, 4H), DMSO-d₆ —1.61 (m, 2H), 1.67 (m, 1H), 1.80 (brm, 6H), 2.04 (m, 1H), 2.49 (s, 3H),2.92 (m, 1H), 4.03 (m, 4H), 5.73 (s, 2H), 6.94 (d, 2H), 7.01 (d, 2H),7.57 (d, 2H), 7.60 (d, 2H), 9.47 (s, 1H) 15 0.86 (t, 3H), 1.31 (brm,4H), DMSO-d₆ 81-89 1.58 (m, 2H), 1.68 (m, 2H), 1.78 (brm, 4H), 2.46 (s,3H), 2.88 (t, 2H), 4.01 (m, 4H), 5.72 (brs, 2H), 6.92 (d, 2H), 6.98 (d,2H), 7.53 (d, 2H), 7.57 (d, 2H), 9.45 (s, 1H) 16 1.36 (s, 9H), 1.57 (m,2H), DMSO-d₆ — 1.78 (brm, 4H), 2.45 (s, 3H), 4.00 (m, 4H), 5.72 (s, 2H),6.91 (d, 2H), 6.98 (d, 2H), 7.55 (d, 2H), 7.58 (d, 2H), 9.44 (s, 1H) 171.26 (t, 3H), 1.66 (m, 2H), CDCl₃ — 1.85 (brm, 4H), 2.83 (s, 3H), 2.86(q, 2H), 4.00 (m, 4H), 4.88 (brs, 1H), 6.87 (d, 2H), 6.91 (d, 2H), 7.46(d, 2H), 7.52 (d, 2H) 18 1..22 (t, 3H), 1.28 (t, 3H), DMSO-d₆ 121-1271.57 (m, 2H), 1.78 (brm, 4H), 2.85 (q, 2H), 4.01 (m, 2H), 5.73 (s, 2H),6.91 (d, 2H), 6.98 (d, 2H), 7.48 (d, 2H), 7.57 (d, 2H), 9.44 (s, 1H) 191.22 (t, 3H), 1.31 (d, 6H), DMSO-d₆ 1.57 (m, 2H), 1.78 (brm, 4H), 2.86(q, 2H), 3.24 (m, 1H), 4.01 (m, 4H), 5.70 (s, 2H), 6.90 (d, 2H), 6.98(d, 2H), 7.49 (d, 2H), 7.58 (d, 2H), 9.43 (s, 1H) 20 1.29 (t, 2H), 1.58(m, 2H), DMSO-d₆ 83-86 1.79 (m, 4H), 2.96 (q, 2H), 4.03 (m, 4H), 5.70(s, 2H), 6.91 (d, 2H), 7.03 (d, 2H), 7.43 (m, 3H), 7.58 (m, 4H), 7.90(m, 2H), 9.43 (s, 1H) 21 1.30 (t, 3H), 1.58 (m, 2H), DMSO-d₆ 146-1531.79 (m, 4H), 2.98 (q, 2H), 4.02 (m, 4H), 5.69 (s, 2H), 6.91 (d, 2H),7.04 (d, 2H), 7.52 (m, 1H), 7.59 (m, 4H), 8.26 (m, 1H), 8.63 (m, 1H),9.10 (s, 1H), 9.42 (s, 1H) 22 1.22 (m, 4H), 1.38 (m, 4H), DMSO-d₆ — 1.58(m, 2H), 1.64 (m, 1H), 1.89 (brm, 6H), 2.01 (m, 2H), 2.87 (m, 3H), 4.01(m, 4H), 5.71 (s, 2H), 6.91 (s, 2H), 6.98 (d, 2H), 7.48 (d, 2H), 7.57(d, 2H), 9.44 (s, 1H) 23 0.86 (t, 3H), 1.21 (t, 3H), DMSO-d₆ 79-88 1.32(brm, 4H), 1.58 (m, 2H), 1.69 (m, 2H), 1.78 (brm, 4H), 2.87 (m, 4H),4.01 (m, 4H), 5.72 (s, 2H), 6.91 (d, 2H), 6.98 (d, 2H), 7.48 (d, 2H),7.58 (d, 2H), 9.44 (s, 1H) 24 1.26 (m, 9H), 1.57 (m, 2H), DMSO-d₆ — 1.79(brm, 4H), 2.92 (q, 2H), 3.31 (m, 1H), 4.01 (m, 4H), 5.71 (brs, 2H),6.91 (d, 2H), 6.98 (d, 2H), 7.43 (d, 2H), 7.57 (d, 2H) 25 1.24 (d, 6H),1.31 (d, 6H), DMSO-d₆ 1.56 (brm, 2H), 1.76 (brm, 5H), 3.21 (m, 1H), 3.90(t, 2H), 4.01 (t, 2H), 5.68 (s, 2H), 6.79 (d, 2H), 6.99 (d, 2H), 7.25(d, 2H), 7.43 (d, 2H), 8.27 (s, 1H) 26 1.31 (d, 6H), 1.58 (brm, 2H),DMSO-d₆ 1.78 (brm, 4H), 3.44 (m, 1H), 4.02 (m, 4H), 5.70 (s, 2H), 6.91(d, 2H), 7.03 (d, 2H), 7.47 (m, 3H), 7.56 (m, 4H), 7.90 (d, 2H), 9.44(s, 1H) 27 1.32 (d, 6H), 1.57 (brm, 2H), DMSO-d₆ 1.78 (brm, 4H), 4.00(m, 4H), 5.71 (s, 2H), 6.91 (d, 2H), 7.04 (d, 2H), 7.51 (m, 1H), 7.58(m, 4H), 8.27 (d, 1H), 8.64 (d, 1H), 9.10 (d, 1H), 9.44 (s, 1H) 28 0.84(t, 3H), 1.23 (d, 6H), DMSO-d₆ 1.32 (brm, 4H), 1.56 (m, 2H), 1.69 (m,2H), 1.78 (brm, 4H), 2.88 (m, 2H), 3.36 (m, 1H), 4.01 (m, 4H), 5.73 (s,2H), 6.91 (d, 2H), 6.98 (d, 2H), 7.43 (d, 2H), 7.58 (d, 2H), 9.45 (s,1H) 29 0.91 (t, 3H), 1.57-1.61 (m, DMSO-d₆ 4H), 1.78 (m, 4H), 2.60 (s,3H), 2.80 (m, 2H), 4.01 (m, 4H), 5.85 (brs, 2H), 6.93 (d, 2H), 6.98 (d,2H), 7.47 (d, 2H), 7.58 (d, 2H), 9.51 (s, 1H) 30 0.83 (t, 3H), 1.30 (m,2H), DMSO-d₆ 138-140 1.53 (m, 4H), 1.78 (brm, 4H), 2.59 (s, 3H), 2.82(m, 2H), 4.00 (m, 4H), 5.74 (brs, 2H), 6.91 (d, 2H), 7.46 (d, 2H), 7.57(d, 2H), 9.45 (s, 1H) 31 0.84 (t, 3H), 1.27 (t, 3H), DMSO-d₆ 80-84 1.31(m, 2H), 1.56 (m, 4H), 1.78 (brm, 4H), 2.83 (t, 2H), 2.92 (m, 2H), 4.01(m, 4H), 5.72 (brs, 2H), 6.91 (d, 2H), 6.98 (d, 2H), 7.47 (d, 2H), 7.58(d, 2H), 9.45 (s, 2H) 32 0.84 (t, 3H), 1.31 (m, 8H), DMSO-d₆ — 1.57 (m,4H), 1.78 (brm, 4H), 2.83 (m, 2H), 3.24 (m, 1H), 4.01 (m, 4H), 5.74(brs, 2H), 6.91 (d, 2H), 6.98 (d, 2H), 7.47 (d, 2H), 7.57 (d, 2H), 9.45(s, 1H) 33 0.86 (t, 3H), 1.33 (m, 2H), 1.61 (m, DMSO-d₆ — 4H), 1.80 (m,4H), 2.92 (t, 2H), 4.01 (m, 4H), 5.72 (brs, 2H), 6.91 (d, 2H), 7.02 (d,2H), 7.46 (m, 3H), 7.59 (m, 4H), 7.91 (d, 2H), 9.45 (s, 1H) 34 0.86 (t,3H), 1.35 (m, 2H), 1.59 (m, DMSO-d₆ 107-118 2H), 1.66 (m, 2H), 1.78 (m,4H), 2.95 (t, 2H), 4.03 (m, 4H), 5.75 (brs, 2H), 6.91 (d, 2H), 7.04 (d,2H), 7.51 (m, 1H), 7.58 (m, 4H), 8.26 (d, 1H), 8.63 (d, 1H), 9.09 (d,1H), 9.45 (s, 1H) 35 0.84 (t, 3H), 1.28 (brm, 6H), DMSO-d₆ — 1.56 (brm,6H), 1.77 (brm, 6H), 2.00 (m, 2H), 2.83 (t, 2H), 2.90 (m, 1H), 4.01 (m,4H), 5.72 (s, 2H), 6.91 (d, 2H), 6.98 (d, 2H), 7.47 (d, 2H), 7.57 (d,2H), 9.44 (s, 1H) 36 0.85 (m, 6H), 1.31 (m, 6H), 1.58 (m, DMSO-d₆ — 4H),1.69 (m, 2H), 1.78 (brm, 4H), 2.83 (t, 2H), 2.88 (t, 2H), 4.01 (m, 4H),5.72 (brs, 2H), 6.91 (d, 2H), 6.98 (d, 2H), 7.47 (d, 2H), 7.57 (d, 2H),9.44 (s, 1H) 37 0.84 (t, 3H), 1.31 (m, 2H), 1.36 (s, DMSO-d₆ — 9H), 1.57(brm, 4H), 1.79 (brm, 4H), 2.83 (m, 2H), 4.01 (m, 4H), 5.74 (brs, 2H),6.91 (d, 2H), 6.97 (d, 2H), 7.48 (d, 2H), 7.58 (d, 2H), 9.45 (s, 1H) 381.56 (m, 2H), 1.78 (brm, 4H), DMSO-d₆ — 2.58 (s, 3H), 4.00 (m, 4H), 4.20(s, 2H), 5.77 (brs, 2H), 6.91 (d, 2H), 6.98 (d, 2H), 7.17 (d, 2H), 7.22(m, 1H), 7.30 (m, 2H), 7.52 (d, 2H), 7.57 (d, 2H), 9.47 (s, 1H) 39 1.28(d, 6H), 1.57 (m, 2H), DMSO-d₆ 108-120 1.77 (brm, 4H), 3.19 (m, 1H),4.00 (m, 2H), 4.21 (s, 2H), 5.70 (s, 2H), 6.90 (d, 2H), 6.98 (d, 2H),7.19 (m, 3H), 7.30 (m, 2H), 7.53 (d, 2H), 7.56 (d, 2H), 9.44 (s, 1H) 401.58 (m, 2H), 1.79 (brm, 4H), DMSO-d₆ — 4.02 (m, 4H), 4.31 (s, 2H), 5.72(brs, 2H), 6.91 (d, 2H), 7.03 (d, 2H), 7.24 (m, 3H), 7.32 (m, 2H), 7.46(m, 3H), 7.58 (d, 2H), 7.64 (d, 2H), 7.89 (m, 2H), 9.44 (s, 2H) 41 1.58(m, 2H), 1.79 (brm, 4H), DMSO-d₆ 134-143 4.02 (m, 4H), 4.34 (s, 2H),5.73 (brs, 2H), 6.91 (d, 2H), 7.04 (d, 2H), 7.25 (m, 3H), 7.33 (,. 2H),7.49 (m, 1H), 7.58 (d, 2H), 7.66 (d, 2H), 8.25 (d, 1H), 8.63 (d, 1H),9.08 (s, 1H), 9.45 (s, 1H) 42 1.65 (m, 2H), 1.86 (m, 4H), DMSO-d₆ 2.72(s, 3H), 3.30 (t, 2H), 3.67 (t, 2H), 4.02 (m, 4H), 5.70 (s, 2H), 6.92(m, 4H), 7.45 (d, 2H), 9.43 (s, 1H) 43 1.58 (brs, 6H), 1.77 (brs, 6H),CDCl₃ 2.07 (brs, 2H), 2.62 (s, 3H), 3.30 (m, 1H), 3.98 (m, 4H),6.75-6.92 (m, 4H), 7.39-7.60 (m, 4H) 44 0.86 (d, 6H), 1.60 (m 2H),DMSO-d₆ 1.78 (m, 5H), 2.61 (s, 3H), 2.72 (d, 2H), 4.01 (m, 4H), 5.77 (s,2H), 6.91 (d, 2H), 6.98 (d, 2H), 7.45 (d, 2H), 7.59 (d, 2H), 9.47 (s,1H) 45 1.14 (m, 2H), 1.48 (brm 6H), DMSO-d₆ — 1.69 (m, 2H), 1.78 (brm,4H), 2.02 (m, 1H), 2.59 (s, 3H), 2.82 (d, 2H), 4.00 (m, 4H), 5.70 (s,2H), 6.90 (d, 2H), 6.97 (d, 2H), 7.46 (d, 2H), 7.57 (d, 2H), 9.44 (s,1H) 46 1.11 (m, 2H), 1.27 (t, 3H), DMSO-d₆ — 1.52 (brm, 6H), 1.70 (m,2H), 1.78 (brm, 4H), 2.03 (m, 1H), 2.83 (d, 2H), 2.92 (q, 2H), 4.00 (m,4H), 5.70 (s, 2H), 6.91 (d, 2H), 6.98 (d, 2H), 7.46 (d, 2H), 7.79 (d,2H), 9.44 (s, 1H) 47 1.11 (m, 2H), 1.31 (d, 6H), DMSO-d₆ — 1.49 (brm,6H), 1.78 (brm, 6H), 2.04 (m, 1H), 2.83 (d, 2H), 3.21 (m, 1H), 4.01 (m,4H), 5.72 (brs, 2H), 6.91 (d, 2H), 6.98 (d, 2H), 7.47 (d, 2H), 7.57 (d,2H), 9.44 (s, 1H) 48 1.15 (m, 2H), 1.50 (brm, 6H), DMSO-d₆ — 1.78 (brm,6H), 2.11 (m, 1H), 2.92 (d, 2H), 4.01 (m, 4H), 5.71 (s, 2H), 6.91 (d,2H), 7.02 (d, 2H), 7.46 (m, 3H), 7.58 (m, 4H), 7.91 (dd, 2H), 9.44 (s,1H) 49 1.16 (m, 2H), 1.55 (brm, 6H), DMSO- — 1.78 (brm, 6H), 2.12 (m,1H), d₆ 2.96 (d, 2H), 4.02 (m, 4H), 5.71 (brs, 2H), 6.91 (d, 2H), 7.04(d, 2H), 7.52 (m, 1H), 7.58 (m, 4H), 8.26 (m, 1H), 8.64 (dd, 1H), 9.10(d, 1H), 9.44 (s, 1H) 50 1.10 (m, 2H), 1.23 (m, 1H), DMSO- 1.46 (brm,11H), 1.77 (brm, d₆ 8H), 2.02 (m, 3H), 2.83 (d, 2H), 2.90 (m, 1H), 4.00(m, 4H), 5.71 (s, 2H), 6.91 (d, 2H), 6.97 (d, 2H), 7.46 (d, 2H), 7.57(d, 2H), 9.44 (s, 1H) 51 0.85 (t, 3H), 1.10 (m, 2H), DMSO- 1.31 (brm,4H), 1.52 (brm, 6H), d₆ 1.58 (brm, 4H), 1.70 (brm, 4H), 2.03 (m, 1H),2.83 (d, 2H), 2.89 (m, 2H), 4.01 (m, 4H), 5.71 (s, 2H), 6.91 (d, 2H),6.98 (d, 2H), 7.46 (d, 2H), 7.57 (d, 2H), 9.44 (s, 1H) 57 1.56 (m, 2H),1.77 (m, 4H), DMSO- 3.98 (m, 4H), 5.72 (s, 2H), d₆ 6.80-6.99 (m, 7H),7.58 (d, 2H), 7.69 (d, 2H), 9.46 (s, 1H) 58 1.57 (m, 2H), 1.77 (m, 4H),DMSO- 2.27 (s, 3H), 3.99 (m, 4H), d₆ 5.72 (s, 2H), 6.70 (s, 2H), 6.91(m, 4H), 7.45 (d, 2H), 7.57 (d, 2H), 9.44 (s, 1H) 59 1.56 (m, 2H), 1.78(m, 2H), DMSO- 2.30 (s, 3H), 4.00 (t, 4H), d₆ 5.71 (s, 2H), 6.91 (d,2H), 6.94 (d, 2H), 7.47 (d, 2H), 7.57 (d, 2H), 9.44 (s, 1H) 60 1.15 (t,3H), 1.57 (m, 2H), DMSO- 1.76 (m, 4H), 2.68 (q, 2H), d₆ 3.99 (m, 4H),5.69 (s, 2H), 6.72 (s, 2H), 6.91 (m, 4H), 7.39 (d, 2H), 7.57 (d, 2H),9.43 (s, 1H) 61 1.17 (d, 6H), 1.56 (m, 2H), DMSO- 1.78 (m, 3H), 3.20 (m,1H), d₆ 4.00 (m, 4H), 5.70 (brm, 1H), 6.91 (m, 4H), 7.35 (m, 2H), 7.57(m, 2H), 9.43 (s, 1H) 62 1.17 (d, 6H), 1.56 (brm, 2H), DMSO-d₆ 1.77(brm, 4H), 3.22 (m, 1H), 4.00 (m, 4H), 5.71 (s, 2H), 6.93 (m, 5H), 7.38(d, 2H), 7.57 (d, 2H), 9.44 (s, 1H) 63 0.83 (t, 3H), 1.30 (m, 2H), 1.48(m, DMSO-d₆ 2H), 1.56 (m, 2H), 1.77 (brm, 4H), 2.65 (t, 2H), 3.99 (m,4H), 5.73 (brs, 2H), 6.72 (s, 2H), 6.91 (m, 4H), 7.38 (d, 2H), 7.57 (d,2H), 9.45 (s, 1H) 64 0.83 (t, 3H), 1.28 (m, 2H), 1.53 (m, DMSO-d₆ 4H),1.78 (m, 4H), 2.69 (m, 2H), 4.00 (m, 4H), 5.73 (brs, 2H), 6.91 (d, 2H),6.95 (d, 2H), 7.42 (d, 2H), 7.57 (d, 2H), 9.45 (s, 1H) 65 1.55 (brm,,2H), 1.77 (brm, 4H), DMSO-d₆ 3.98 (m, 4H), 4.02 (s, 1H), 5.79 (s, 2H),6.79 (s, 2H), 6.91 (m, 4H), 7.19 (m, 3H), 7.29 (m, 2H), 7.43 (d, 2H),7.57 (d, 2H), 9.47 (s, 1H) 66 1.55 (m, 2H), 1.77 (brm, 4H), DMSO-d₆ 4.99(m, 4H), 4.05 (s, 2H), 5.71 (s, 2H), 4.92 (m, 4H), 7.19 (m, 3H), 7.29(m, 2H), 7.45 (d, 2H), 7.57 (d, 2H), 9.44 (s, 1H) 67 1.09 (brm, 2H),1.48 (brm, 4H), DMSO-d₆ 1.56 (m, 2H), 1.69 (m, 2H), 1.77 (brm, 4H), 1.97(m, 1H), 2.65 (d, 2H), 3.98 (m, 4H), 5.70 (s, 2H), 6.72 (s, 2H), 6.90(m, 4H), 7.38 (d, 2H), 7.57 (d, 2H), 9.44 (s, 1H) 68 0.84 (t, 3H), 1.11(m, 2H), DMSO-d₆ 1.43-1.78 (brm, 17H), 2.04 (m, 4H), 2.24 (m, 2H), 2.85(m, 5H), 4.01 (m, 4H), 5.70 (s, 2H), 6.90 (d, 2H), 6.98 (d, 2H), 7.47(d, 2H), 7.57 (d, 2H), 9.44 (s, 1H) 69 1.11 (d, 6H), 1.59 (m, 2H), 1.79(m, DMSO-d₆ 4H), 2.42 (s, 3H), 2.72 (m, 1H), 4.02 (m, 4H), 5.72 (s, 2H),6.93 (d, 2H), 7.00 (d, 2H), 7.56 (m, 4H), 9.45 (s, 1H), 12.00 (s, 1H) 701.25 (d, 6H), 1.58 (m, 2H), 1.80 (m, DMSO-d₆ 4H), 2.50 (m, 4H), 3.33 (m,1H), 3.60 (m, 4H), 3.76 (s, 2H), 4.01 (m, 4H), 5.70 (s, 2H), 7.00 (m,4H), 7.45 (d, 2H), 7.60 (d, 2H), 9.44 (s, 1H) 71 1.56 (m, 2H), 1.78(brm, 4H), DMSO-d₆ 3.92 (s, 2H), 4.00 (m, 1H), 4.21 (s, 2H), 5.70 (s,2H), 6.90 (d, 2H), 6.97 (d, 2H), 7.21 (m, 3H), 7.30 (m, 2H), 7.52 (d,2H), 7.57 (d, 2H), 9.44 (s, 1H) 72 0.84 (t, 3H), 1.42 (m, 2H), 1.56 (m,DMSO-d₆ 2H), 1.67 (m, 2H), 1.78 (brm, 4H), 2.00 (m, 4H), 2.24 (m, 2H),2.46 (s, 3H), 2.89 (m, 3H), 4.00 (m, 4H), 5.71 (m, 2H), 6.90 (d, 2H),6.98 (d, 2H), 7.56 (m, 4H), 9.44 (s, 1H) 73 1.25 (d, 6H), 1.57 (m, 2H),1.79 (m, DMSO-d₆ 4H), 3.35 (m, 1H), 3.96-4.04 (m, 6H), 5.74 (s, 2H),6.91 (d, 2H), 6.98 (d, 2H), 7.93 (d, 2H), 7.58 (d, 2H) 74 1.61 (m, 2H),1.81 (m, 4H), 2.66 (s, CDCl₃ 3H), 3.95 (m, 4H), 5.16 (s, 1H), 5.17 (d,1H), 5.42 (d, 1H), 6.84 (m, 3H), 6.92 (d, 2H), 7.51 (d-d, 4H) 75 1.58(m, 2H), 1.79 (m, 4H), 2.63 (s, 3H), 4.01 (m, 4H), 4.12 (t, 1H), 4.67(m, 2H), 5.70 (brs, 2H), 6.98 (m, 2H), 7.50 (m, 2H), 7.58 (m, 2H), 8.23(s, 1H) 76 1.57 (m, 2H), 1.80 (m, 4H), 2.65 (s, 3H), 3.32 (s, 3H), 4.01(m, 4H), 4.58 (s, 2H), 6.93 (m, 2H), 7.01 (m, 2H), 7.56 (m, 4H), 9.45(brs, 1H) 77 1.57 (m, 2H), 1.79 (m, 4H), 3.36 (m, DMSO-d₆ 2H), 3.77 (m,2H), 4.00 (m, 4H), 5.73 (s, 2H), 6.91 (m, 4H), 7.42 (d, 2H), 7.58 (d,2H), 9.47(s, 1H) 78 1.58 (m, 2H), 1.79 (m, 4H), 4.01 (m, DMSO-d₆ 4H),6.82-7.75 (m, 11H) 79 1.59 (m, 2H), 1.81 (m, 4H), 4.05 (m, DMSO-d₆ 4H),5.44 (d, 1H), 5.71 (d, 1H), 5.85 (brs, 2H), 6.94 (m, 3H), 7.07 (m, 2H),7.61 (m, 4H), 8.33 (m, 1H), 8.68 (m, 1H), 9.16 (brs, 1H), 9.52 (brs, 1H)80 1.60 (m, 2H), 1.81 (m, 4H), 3.44 (m, DMSO-d₆ 2H), 3.94 (m, 2H),4.02-4.06 (m, 4H), 5.75 (brs, 2H), 6.91 (m, 2H), 7.06 (m, 2H), 7.61 (m,4H), 8.30 (m, 1H), 8.68 (m, 1H), 9.13 (m, 1H), 9.46 (m, 1H) 81 1.40 (m,2H), 1.55-1.59 (m, 4H), DMSO-d₆ 1.77-1.81 (m, 6H), 2.01 (m, 2H),3.22-3.31 (m, 1H), 4.00-4.02 (m, 4H), 5.72 (s, 2H), 6.92 (m, 4H), 7.57(d, 2H), 7.83 (d, 2H) 82 1.21 (t, 3H), 1.58 (m, 2H), 1.78 (m, DMSO-d₆4H), 2.85 (q, 2H), 3.93 (s, 2H), 4.00 (m, 4H), 5.70 (s, 2H), 6.90 (d,2H), 6.97 (d, 2H), 7.48 (d, 2H), 7.58 (d, 2H), 9.43 (s, 1H) 83 1.25 (d,6H), 1.57 (m, 2H), 1.80 (m, DMSO-d₆ 4H), 1.91 (m, 2H), 2.17 (m, 2H),3.05 (m, 2H), 3.37 (m, 4H), 4.02-4.09 (m, 4H), 7.00 (d, 2H), 7.13 (d,2H), 7.44 (d, 2H), 7.67 (d, 2H)

2. Benzamidine (R₅=H) Examples 52 to 56

Compound (12) prepared according to the same method as that in thePreparative Example 1-6 was reacted in the same manner as Example 2,obtaining the title compounds shown I Table 2.

Table 2 shows the title compounds, reactants and ¹H-NMR data.

TABLE 2 Acid example name chloride Thioamide Alkylhalide NMR solvent mp52 4-5-[4-(2-methyl- acetylchloride thioacetamide 1.57 (brm, 2H), 1.79(brm, 4H), DMSO-d₆ 1,3-thiazol-4- 2.68 (s, 3H), 4.01 (t, 2H),yl)phenoxy]pentoxy- 4.11 (t, 2H), 6.96 (d, 2H), benzamidine 7.13 (d,2H), 7.81 (m, 4H) 53 4-5-[4-(2- acetylchloride thioisobutramide 1.35 (d,6H), 1.56 (brm, 2H), DMSO-d₆ isopropyl-1,3- 1.78 (brm, 4H), 3.30 (m,1H), thiazol-4- 4.02 (m, 4H), 6.95 (m, 4H), yl)phenoxy]pentoxy- 7.77 (s,1H), 7.83 (m, 4H) benzamidine 54 4-5-[4-(2,5- propionylchloridethioacetamide 1.57 (brm, 2H), 1.79 (brm, 4H), DMSO-d₆ dimethyl-1,3- 2.68(s, 3H), 4.01 (t, 2H), thiazol-4- 4.11 (t, 2H), 6.96 (d, 2H),yl)phenoxy]pentoxy- 7.12 (d, 2H), 7.73 (s, 1H), benzamidine 7.81 (m, 4H)55 4-5-[4-(5-ethyl-2- butrylchloride thioisobutramide 1.32 (d, 6H), 1.59(m, 2H), DMSO-d₆ isopropyl-1,3- 1.79 (m, 4H), 2.47 (s, 3H), thiazol-4-3.21 (m, 1H), 4.02 (t, 2H), yl)phenoxy]pentoxy- 4.09 (t, 2H), 6.98 (d,2H), benzamidine 7.09 (d, 2H), 7.55 (d, 2H), 7.74 (d, 2H) 564-5-[4-(5-ethyl-2- butrylchloride thiobenzamide 1.29 (t, 3H), 1.59 (m,2H), DMSO-d₆ phenyl-1,3- 1.81 (brm, 4H), 2.95 (q, 2H), thiazol-4- 4.04(t, 2H), 4.11 (t, 2H0, yl)phenoxy]pentoxy- 7.03 (d, 2H), 7.15 (d, 2H),benzamidine 7.47 (m, 3H), 7.59 (d, 2H), 7.84 (d, 2H), 7.91 (m, 2H)

Examples 84 to 117

Compound (16) prepared according to the same method as that in thePreparative Example 2-2 was reacted in the same manner as Example 1,obtaining the title compounds shown I Table 3.

Table 3 shows the title compounds, reactants and ¹H-NMR data.

TABLE 3 Acid example name chloride Thioamide Alkylhalide NMR solvent mp84 N-hydroxy-4-5-[4- acetylchloride thiourea iodoethane 1.17 (t, 3H),1.55 (brm, 2H), DMSO-d₆ (2-ethylamino- 1.77 (brm, 2H), 3.25 (m, 2H),1,3-thiazol-4- 3.99 (m, 4H), 5.73 (s, 2H), yl)phenoxy]pentoxy- 6.84 (s,1H), 6.90 (m, 4H), benzamidine 7.57 (d, 2H), 7.71 (d, 2H) 85N-hydroxy-4-5-[4- acetylchloride thiourea ethansulfonylchloride 1.20 (t,3H), 1.55 (brm, 2H), DMSO-d₆ (2- 1.77 (brm, 4H), 3.02 (q, 2H),ethansulfonylamino- 4.00 (m, 4H), 5.77 (brm, 2H), 1,3-thiazol-4- 6.91(d, 2H), 6.98 (d, 2H), yl)phenoxy]pentoxy- 7.00 (s, 1H), 7.57 (d, 2H),benzamidine 7.65 (d, 2H), 9.47 (brs, 1H), 12.86 (s, 1H) 86N-hydroxy-4-5- propionylchloride thiourea iodomethane 1.56 (m, 2H), 1.77(m, 4H), DMSO-d₆ [4-(5-methyl-2- 2.29 (s, 3H), 2.77 (d, 3H),methylamino-1,3- 3.99 (m, 4H), 5.72 (s, 2H), thiazol-4- 6.91 (m, 4H),7.22 (m, 1H), yl)phenoxy]pentoxy- 7.48 (d, 2H), 7.50 (d, 2H),benzamidine 9.44 (s, 1H) 87 N-hydroxy-4-5-[4- propionylchloride thioureaiodoethane 1.12 (t, 3H), 1.56 (m, 2H), DMSO-d₆ (2-ethylamino-5- 1.78 (m,4H), 2.28 (s, 3H), methyl-1,3- 3.18 (p, 2H), 3.99 (t, 4H), thiazol-4-5.72 (s, 2H), 6.94 (m, 4H), yl)phenoxy]pentoxy- 7.27 (t, 1H), 7.47 (d,2H), benzamidine 7.57 (d, 2H), 9.44 (s, 1H) 88 N-hydroxy-4-5-[4-propionylchloride thiourea propylbromide 0.89 (t, 3H), 1.54 (m, 4H),DMSO-d₆ (5-methyl-2- 1.78 (m, 4H), 2.28 (s, 3H), propylamino-1,3- 3.12(m, 2H), 3.99 (m, 4H), thiazol-4- 5.72 (s, 1H), 6.92 (m, 4H),yl)phenoxy]pentoxy- 7.32 (t, 1H), 7.47 (d, 2H), benzamidine 7.57 (d,2H), 9.44 (s, 1H) 89 N-hydroxy-4-5-[4- cyclopentyl- thioureaniconoylchloride 1.15 (m, 2H), 1.57 (brm, 6H), DMSO-d₆ (5-propionylchloride 1.77 (brm, 6H), 2.10 (m, 1H), cyclopentylmethyl- 2.85(d, 2H), 4.00 (m, 4H), 2-(3- 5.72 (brs, 2H), 6.91 (d, 2H),pyridylcarbonyl)amino- 7.00 (d, 2H), 7.51 (d, 2H), 1,3-thiazol- 7.58 (d,2H), 7.38 (m, 1H), 4- 8.40 (d, 1H), 8.77 (d, 1H), yl)phenoxy]pentoxy-9.19 (s, 1H), 9.44 (s, 1H), benzamidine 12.83 (s, 1H) 90N-hydroxy-4-5-[4- propionylchloride thiourea acetoxyacetyl 1.56 (brm,2H), 1.78 (brm, 4H), DMSO-d₆ (2- chloride 2.42 (s, 3H), 4.01 (m, 4H),hydroxyacetylamino- 4.10 (d, 2H), 5.47 (t, 1H), 5-methyl-1,3- 5.73 (brs,2H), 6.92 (d, 2H), thiazol-4- 6.98 (d, 2H), 7.55 (m, 4H),yl)phenoxy]pentoxy- 9.45 (s, 1H), 11.67 (s, 1H) benzamidine 91N-hydroxy-4-5-[4- propionylchloride thiourea isoniconoylchloride 1.57(brm, 4H), 1.79 (brm, 4H), DMSO-d₆ (5-methyl-2-(4- 2.48 (s, 3H), 4.02(m, 4H), pyridylcarbonyl)amino- 5.73 (brm, 2H), 6.91 (d, 2H),1,3-thiazol- 7.01 (d, 2H), 7.58 (m, 4H), 4- 7.98 (dd, 2H), 8.78 (dd,2H), yl)phenoxy]pentoxy- 9.45 (s, 1H) benzamidine 92 N-hydroxy-4-5-[4-propionylchloride thiourea niconoylchloride 1.58 (m, 2H), 1.79 (m, 4H),DMSO-d₆ (5-methyl-2-(3- 2.46 (s, 3H), 4.01 (m, 4H),pyridylcarbonyl)amino- 5.74 (s, 2H), 6.91 (d, 2H), 1,3-thiazol-4- 7.00(d, 2H), 7.57 (m, 4H), yl)phenoxy]pentoxy- 8.41 (d, 1H), 8.77 (d, 1H),benzamidine 9.20 (d, 1H), 9.46 (brs, 1H), 12.80 (brs, 1H) 93N-hydroxy-4-5-[4- propionylchloride thiourea ethansulfonylchloride 0.94(t, 3H), 1.56 (m, 2H), DMSO-d₆ (2- 1.78 (brm, 4H), 2.18 (s, 3H),ethansulfonylamino- 2.98 (q, 2H), 4.01 (m, 4H), 5-methyl-1,3- 5.73 (s,2H), 6.90 (d, 2H), thiazol-4- 7.01 (d, 2H), 7.38 (d, 2H),yl)phenoxy]pentoxy- 7.57 (d, 2H), 9.44 (s, 1H), benzamidine 12.52 (s,1H) 94 N-hydroxy-4-(5-4- propionylchloride thiourea 2- 1.58 (m, 2H),1.80 (m, 4H), DMSO-d₆ [2-(2- chloroethylmethylester 2.30 (s, 3H), 3.26(s, 3H), methoxyethyl)amino- 3.39 (m, 2H), 3.37 (m, 2H), 5-methyl-1,3-4.01 (m, 4H), 5.71 (s, 2H), thiazol-4- 6.90 (d, 2H), 6.96 (d, 2H),yl]phenoxypentoxy)- 7.48 (d, 2H), 7.58 (d, 2H), benzamidine 9.44 (s, 1H)95 N-hydroxy-4-5-[4- butrylchloride thiourea ethansulfonylchloride 1.13(t, 3H), 1.21 (t, 3H), DMSO-d₆ (2- 1.57 (m, 2H), 1.78 (brm, 4H),ethansulfonylamino- 2.59 (q, 2H), 2.99 (q, 2H), 5-ethyl-1,3- 4.01 (m,4H), 5.70 (s, 2H), thiazol-4- 6.90 (s, 2H), 7.01 (d, 2H),yl)phenoxy]pentoxy- 7.35 (d, 2H), 7.57 (d, 2H), benzamidine 9.43 (s,1H), 12.50 (brs, 1H) 96 N-hydroxy-4-5-[4- butrylchloride thioureaiodomethane 1.15 (t, 3H), 1.57 (m, 2H), DMSO-d₆ (5-ethyl-2- 1.78 (m,4H), 2.70 (q, 2H), methylamino-1,3- 2.78 (d, 3H), 3.99 (m, 4H),thiazol-4- 5.80 (brs, 2H), 6.92 (m, 4H), yl)phenoxy]pentoxy- 7.25 (q,1H), 7.42 (d, 2H), benzamidine 7.58 (d, 2H), 9.48 (s, 1H) 97N-hydroxy-4-5-[4- butrylchloride thiourea iodoethane 1.41 (m, 6H), 1.57(m, 2H), DMSO-d₆ (5-ethyl-2- 1.78 (t, 4H), 2.69 (q, 2H), ethylamino-1,3-3.19 (q, 2H), 3.99 (t, 4H), thiazol-4- 5.69 (s, 2H), 6.92 (m, 4H),yl)phenoxy]pentoxy- 7.30 (t, 1H), 7.41 (d, 2H), benzamidine 7.57 (d,2H), 9.43 (s, 1H) 98 N-hydroxy-4-5-[4- butrylchloride thioureapropylbromide 0.89 (t, 3H), 1.15 (t, 3H), DMSO-d₆ (5-ethyl-2- 1.55 (brm,4H), 1.77 (brm, 4H), propylamino-1,3- 2.68 (q, 2H), 3.12 (m, 2H),thiazol-4- 3.98 (m, 4H), 5.72 (s, 2H), yl)phenoxy]pentoxy- 6.92 (m, 4H),7.35 (t, 1H), benzamidine 7.40 (d, 2H), 7.57 (d, 2H), 9.44 (s, 1H) 99N-hydroxy-4-5-[4- butrylchloride thiourea methoxyacetyl 1.23 (t, 3H),1.57 (m, 2H), DMSO-d₆ (5-ethyl-2- chloride 1.78 (brm, 4H), 2.84 (q, 2H),methoxyacetylamino- 3.33 (s, 3H), 4.00 (m, 4H), 1,3-thiazol-4- 4.11 (s,2H), 5.70 (s, 2H), yl)phenoxy]pentoxy- 6.90 (d, 2H), 6.98 (d, 2H),benzamidine 7.47 (d, 2H), 7.82 (d, 2H), 9.43 (s, 1H), 11.96 (s, 1H) 100N-hydroxy-4-5-[4- butrylchloride thiourea isoniconoylchloride 1.26 (t,3H), 1.57 (m, 2H), DMSO-d₆ (5-ethyl-2-(4- 1.79 (brm, 4H), 2.88 (q, 2H),(pyridylcarbonyl)amino- 4.00 (m, 4H), 5.74 (s, 2H), 1,3-thiazol-4- 6.91(d, 2H), 7.01 (d, 2H), yl)phenoxy]pentoxy- 7.52 (d, 2H), 7.55 (d, 2H),benzamidine 7.98 (d, 2H), 8.79 (d, 2H), 9.45 (s, 1H), 12.92 (s, 1H) 101N-hydroxy-4-5-[4- butrylchloride thiourea niconoylchloride 1.26 (t, 3H),1.57 (brm, 2H), DMSO-d₆ (5-ethyl-2-(3- 1.79 (brm, 4H), 2.88 (q, 2H),pyridylcarbonyl)amino- 4.00 (m, 4H), 5.71 (brs, 2H), 1,3-thiazol-4- 6.91(d, 2H), 7.01 (d, 2H), yl)phenoxy]pentoxy- 7.56 (m, 5H), 8.40 (m, 1H),benzamidine 8.77 (dd, 1H), 9.20 (d, 1H), 9.43 (s, 1H), 12.82 (s, 1H) 102N-hydroxy-4-5-[4- butrylchloride thiourea 2- 1.14 (t, 3H), 1.60 (m, 2H),DMSO-d₆ (5-ethyl-2-(2- chloroethylmethylester 1.78 (m, 4H), 2.69 (m,2H), methoxyethyl)amino- 3.26 (s, 3H), 3.40 (m, 2H), 1,3-thiazol-4- 3.38(m, 2H), 4.02 (m, 4H), yl)phenoxy]pentoxy- 5.67 (s, 2H), 5.75 (s, 1H),benzamidine 6.90-7.00 (m, 4H), 7.40 (d, 2H), 7.58 (d, 2H), 9.45 (s, 1H)103 N-hydroxy-4-5-[4- isovalerylchloride thiourea iodomethane 1.17 (d,6H), 1.56 (brm, 2H), DMSO-d₆ (5-isopropyl-2- 1.77 (brm, 2H), 2.77 (d,3H), methylamino-1,3- 3.21 (m, 1H), 5.72 (s, 2H), thiazol-4- 6.91 (d,2H), 6.94 (d, 2H), yl)phenoxy]pentoxy- 7.25 (m, 1H), 7.38 (d, 2H),benzamidine 7.57 (d, 2H), 9.44 (s, 1H) 104 N-hydroxy-4-5-[4-isovalerylchloride thiourea iodoethane 0.85 (m, 3H), 1.17 (d, 6H),DMSO-d₆ (2-ethylamino-5- 1.58 (m, 2H), 1.82 (m, 4H), isopropyl-1,3- 3.20(m, 3H), 4.04 (m, 4H), thiazol-4- 6.95 (m, 4H), 7.39 (m, 2H),yl)phenoxy]pentoxy- 7.82 (m, 2H) benzamidine 105 N-hydroxy-4-5-[4-hexanoylchloride thiourea iodomethane 0.83 (t, 3H), 1.30 (m, 2H),DMSO-d₆ (5-butyl-2- 1.48 (m, 2H), 1.56 (m, 2H), methylamino-1,3- 1.77(m, 4H), 2.67 (t, 2H), thiazol-4- 2.78 (d, 3H), 4.01 (m, 4H),yl)phenoxy]pentoxy- 5.72 (brs, 2H), 6.92 (m, 4H), benzamidine 7.26 (m,1H), 7.41 (d, 2H), 7.58 (d, 2H), 9.44 (s, 1H) 106 N-hydroxy-4-5-[4-hexanoylchloride thiourea iodoethane 0.83 (t, 3H), 1.13 (t, 3H), DMSO-d₆(5-butyl-2- 1.28 (m, 2H), 1.53 (m, 4H), ethylamino-1,3- 1.78 (m, 4H),2.64 (t, 2H), thiazol-4- 3.18 (m, 2H), 3.99 (m, 4H), yl)phenoxy]pentoxy-5.75 (brs, 2H), 6.92 (m, 4H), benzamidine 7.31 (t, 1H), 7.40 (d, 2H),7.57 (d, 2H), 9.46 (s, 1H) 107 N-hydroxy-4-5-[4- hydrocinnamoyl thioureaiodomethane 1.55 (m, 2H), 1.76 (brm, 4H), DMSO-d₆ (5-benzyl-2- chloride2.77 (d, 3H), 3.98 (m, 4H), methylamino-1,3- 4.03 (s, 2H), 5.72 (brs,2H), thiazol-4- 6.91 (m, 4H), 7.20 (m, 3H), yl)phenoxy]pentoxy- 7.29 (m,3H), 7.46 (d, 2H), benzamidine 7.57 (d, 2H), 9.44 (s, 1H) 108N-hydroxy-4-5- hydrocinnamoyl thiourea iodoethane 1.14 (t, 3H), 1.55 (m,2H), 1.77 (brm, DMSO-d₆ [4-(5-benzyl-2- chloride 4H), 3.18 (m, 2H), 4.00(m, 4H), ethylamino-1,3- 4.03 (s, 2H), 6.94 (m, 4H), 7.17 (m, thiazol-4-3H), 7.29 (m, 2H), 7.39 (t, 1H), yl)phenoxy]pentoxy- 7.45 (d, 2H), 7.58(d, 2H), 9.64 (s, benzamidine 1H) 109 N-hydroxy-4-5- cyclopentyl-thiourea iodomethane 1.10 (brm, 2H), 1.49 (brm, 4H), DMSO-d₆ [4-(5-propionylchloride 1.56 (m, 2H), 1.69 (m, 2H), 1.78 (m,cyclopentylmethyl- 4H), 1.97 (m, 1H), 2.66 (d, 2H), 2-methylamino- 2.78(d, 3H), 3.99 (m, 4H), 5.71 (s, 1,3-thiazol-4- 2H), 6.92 (m, 4H), 7.25(m, 1H), yl)phenoxy]pentoxy- 7.40 (d, 2H), 7.57 (d, 2H), 9.44 (s,benzamidine 1H 110 N-hydroxy-4-5- cyclopentyl- thiourea iodomethane 1.13(m, 5H), 1.49 (m, 6H), 1.69 (m, DMSO-d₆ [4-(5- propionylchloride 2H),1.77 (m, 4H), 1.97 (m, 1H), cyclopentylmethyl- 2.66 (d, 2H), 3.19 (m,2H), 3.99 (m, 2-ethylamino- 4H), 5.70 (s, 2H), 6.91 (m, 4H),1,3-thiazol-4- 7.29 (t, 1H), 7.40 (d, 2H), 7.57 (d, yl)phenoxy]pentoxy-2H), 9.44 (s, 1H) benzamidine 111 N-hydroxy-4-5- cyclopentyl- thioureapropylbromide 0.88 (t, 3H), 1.10 (brm, 2H), DMSO-d₆ [4-(5-propionylchloride 1.55 (brm, 8H), 1.77 (brm, 6H), cyclopentylmethyl-1.97 (m, 1H), 2.65 (d, 2H), 3.11 (m, 2-propylamino- 2H), 3.99 (m, 4H),5.70 (s, 2H), 1,3-thiazol-4- 6.90 (d, 2H), 6.92 (d, 2H), 7.33 (t,yl)phenoxy]pentoxy- 1H), 7.39 (d, 2H), 7.57 (d, 2H), benzamidine 9.44(s, 1H) 112 N-hydroxy-4-5- cyclopentyl- thiourea isoniconoylchloride1.55 (m, 2H), 1.49 (brm, 6H), DMSO-d₆ [4-(5- propionylchloride 1.77(brm, 6H), 2.10 (m, 1H), 2.86 (d, cyclopentylmethyl- 2H), 4.00 (m, 4H),5.74 (s, 2H), 2-(4- 6.91 (d, 2H), 7.01 (d, 2H), 7.51 (d,pyridylcarbonyl)amino- 2H), 7.58 (d, 2H), 7.97 (d, 2H), 1,3- 8.79 (d,2H), 9.46 (s, 1H), 12.91 (s, thiazol-4- 1H) yl)phenoxy]pentoxy-benzamidine 113 N-hydroxy-4-5- cyclopentylacetyl thiourea propylbromide0.89 (t, 3H), 1.55-1.62 (m, 8H), DMSO-d₆ [4-(5- chloride 1.77-1.80 (m,8H), 3.31-3.37 (m, 3H), cyclopentyl-2- 4.00-4.02 (m, 4H), 6.90-7.05 (m,4H), propylamino-1,3- 7.39-7.80 (m, 4H) thiazol-4- yl)phenoxy]pentoxy-benzamidine 114 N-hydroxy-4-5- isovalerylchloride thiourea 3- 0.82 (d,6H), 1.17-1.25 (m, 2H), DMSO-d₆ [4-(5-isopropyl- bromomethylpyridin1.78-1.80 (m, 4H), 3.25 (m, 1H), 3.37 (s, 2-[(pyridin-3- 2H), 4.01 (m,4H), 6.94-7.83 (m, 12H) ylmethyl)amino]- 1,3-thiazol-4-yl)phenoxy]pentoxy- benzamidine 115 N-hydroxy-4-5- 4-chlorobutryl-thiourea iodomethane 1.58 (m, 2H), 1.80 (m, 4H), 2.81 (s, DMSO-d₆[4-(5-(2- chloride 3H), 3.13 (m, 2H), 3.78 (m, 2H), chloroethyl)-2- 4.01(m, 4H), 5.73 (m, 2H), 6.93 (m, methylamino-1,3- 4H), 7.44 (m, 2H), 7.59(m, 2H), thiazol-4- 9.46 (s, 1H) yl)phenoxy]pentoxy- benzamidine 116N-hydroxy-4-5- propyl thiourea iodomethane 1.57 (m, 2H), 1.77-1.81 (m,4H), DMSO-d₆ [4-(2- chloride 2.86 (d, 3H), 3.99-4.01 (m, 4H),methylamino-1,3- 5.72 (s, 2H), 6.88-6.93 (m, 5H), thiazol-4- 7.59 (d,2H), 7.74 (d, 2H), 9.46 (s, yl)phenoxy]pentoxy- 1H) benzamidine 117N-hydroxy-4-5- butyryl thiourea 3- 1.24 (t, 3H), 1.57 (m, 2H), 1.79 (m,DMSO-d₆ [4-(5-ethyl-2- chloride bromomethylpyridin 4H), 2.87 (q, 2H),3.79 (s, 2H), [(pyridin-3- 3.91 (s, 2H), 4.02 (m, 4H), 5.74 (s,ylmethyl)amino- 1H), 6.94 (d-d, 4H), 7.35 (m, 1H), 1,3-thiazol-4- 7.48(d, 2H), 7.77 (d, 1H), 7.82 (d, yl)phenoxy]pentoxy- 2H), 8.45 (d, 1H),8.54 (s, 1H) benzamidine

Examples 118 to 163

Compound (18) prepared according to the same method as that in thePreparative Example 3 was reacted in the same manner as Example 1,obtaining the title compounds shown I Table 4.

Table 4 shows the title compounds, reactants and ¹H-NMR data.

TABLE 4 Acid example name chloride Thioamide Alkylhalide NMR solvent mp118 N-hydroxy-4-5-[4- acetylchloride thiourea ethansulfonyl- 1.20 (t,3H), 1.57 (m, 2H), 1.79 (m, DMSO-d₆ (2-(ethansulfonyl- chloride 4H),3.50 (m, 5H), 4.01 (m, 4H), methyl-amino)-1,3- 5.71 (s, 2H), 6.96 (m,4H), 7.55 (m, thiazol-4- 2H), 7.81 (m, 3H), 9.44 (s, 1H)yl)phenoxy]pentoxy- benzamidine 119 N-hydroxy-4-5-[4- acetylchloridethiourea chloroethyl- 1.56 (brm, 2H), 1.78 (brm, 4H), DMSO-d₆(2-methyl-(2- morpholine 2.43 (m, 4H), 2.55 (m, 2H), 3.05 (s,morpholinoethyl)amino- 3H), 3.52 (m, 4H), 3.60 (m, 2H), 1,3-thiazol-4-3.99 (brm, 4H), 5.70 (s, 2H), yl)phenoxy]pentoxy- 6.91 (m, 4H), 6.95 (s,1H), 7.57 (d, benzamidine 2H), 7.73 (d, 2H), 9.44 (s, 1H) 120N-hydroxy-4-5-[4- propionylchloride thiourea bromoethanol 1.56 (m, 2H),1.78 (brm, 4H), DMSO-d₆ (2-(2- 2.31 (s, 3H), 3.02 (s, 3H), 3.44 (t,hydroxyethyl)- 2H), 3.59 (q, 2H), 4.00 (t, 4H), methyl-amino]-5- 4.79(t, 1H), 5.71 (s, 2H), 6.90 (d, methyl-1,3-thiazol- 2H), 6.94 (d, 2H),7.48 (d, 2H), 4- 7.57 (d, 2H), 9.43 (s, 1H) yl)phenoxy]pentoxy-benzamidine 121 N-hydroxy-4-5-[4- propionylchloride thioureabromoethanol 1.14 (t, 3H), 1.56 (m, 2H), DMSO-d₆ (2-(ethyl-(2- 1.78(brm, 4H), 2.31 (s, 3H), hydroxyethyl)- 3.41 (m, 4H), 3.58 (m, 2H), 4.00(m, amino)-5-methyl- 4H), 4.82 (t, 1H), 5.73 (s, 2H), 1,3-thiazol-4-6.91 (d, 2H), 6.94 (d, 2H), 7.48 (d, yl)phenoxy]pentoxy- 2H), 7.57 (d,2H), 9.45 (s, 1H) benzamidine 122 N-hydroxy-4-5-[4- propionylchloridethiourea 2-chloroethyl- 1.59 (m, 2H), 1.79 (m, 4H), 2.32 (s, DMSO-d₆(2-(bis-(2- methylester 3H), 3.26 (s, 6H), 3.55 (s, 8H), methoxyethyl)-4.03 (m, 4H), 5.70 (s, 2H), 6.91 (d, amino)-5-methyl- 2H), 6.95 (d, 2H),7.49 (d, 2H), 1,3-thiazol-4- 7.82 (d, 2H), 9.44 (s, 1H)yl)phenoxy]pentoxy- benzamidine 123 N-hydroxy-4-5-[4- propionylchloridethiourea chloroethyl- 1.56 (m, 2H), 1.77 (brm, 4H), DMSO-d₆ (5-methyl-2-morpholine 2.32 (s, 3H), 2.41 (brm, 4H), (methyl-(2- 2.51 (m, 2H), 2.99(s, 3H), morpholinoethyl)- 3.51 (brm, 4H), 3.99 (t, 4H),amino)-1,3-thiazol- 5.70 (s, 2H), 6.90 (d, 2H), 6.94 (d, 4- 2H), 7.48(d, 2H), 7.57 (d, 2H), yl)phenoxy]pentoxy- 9.44 (s, 1H) benzamidine 124N-hydroxy-4-5-[4- propionylchloride thiourea chloroethyl- 1.15 (t, 3H),1.56 (m, 2H), DMSO-d₆ (2-(ethyl-1-(2- morpholine 1.77 (brm, 4H), 2.31(s, 3H), morpholinoethyl)- 2.42 (brm, 4H), 2.52 (m, 2H),amino)-5-methyl- 3.40 (m, 2H), 3.49 (m, 2H), 1,3-thiazol-4- 3.54 (brm,4H), 3.99 (m, 4H), yl)phenoxy]pentoxy- 5.71 (brs, 2H), 6.90 (d, 2H),benzamidine 6.94 (d, 2H), 7.48 (d, 2H), 7.57 (d, 2H), 9.44 (s, 1H) 125N-hydroxy-4-5-[4- propionylchloride thiourea benzyl 1.57 (m, 2H), 1.77(brm, 4H), DMSO-d₆ (2-(benzyl-methyl- bromide 2.29 (s, 3H), 2.98 (s,3H), 3.99 (m, amino)-5-methyl- 4H), 4.64 (s, 2H), 5.70 (s, 2H),1,3-thiazol-4- 6.90 (d, 2H), 6.94 (d, 2H), 7.30 (m, yl)phenoxy]pentoxy-5H), 7.51 (d, 2H), 7.57 (d, 2H), benzamidine 9.44 (s, 1H) 126N-hydroxy-4-5-[4- propionylchloride thiourea 3-bromomethyl- 1.56 (brm,2H), 1.77 (brm, 4H), DMSO-d₆ (5-methyl-2- pyridin 2.33 (s, 3H), 3.00 (s,3H) 4.00 (m, (methyl-pyridin-3- 4H), 4.68 (s, 2H), 5.71 (s, 2H),yl-methyl-amino)- 6.90 (d, 2H), 6.95 (d, 2H), 7.36 (m, 1,3-thiazol-4-1H), 7.51 (d, 2H), 7.57 (d, 2H), yl)phenoxy]pentoxy- 7.72 (d, 1H), 8.48(d, 1H), 8.55 (s, benzamidine 1H), 9.44 (s, 1H) 127 N-hydroxy-4-5-[4-propionylchloride thiourea benzyl 1.12 (t, 3H), 1.56 (brm, 2H), DMSO-d₆(2-(benzyl-ethyl- bromide 1.77 (brm, 4H), 2.31 (s, 3H), amino)-5-methyl-3.40 (q, 2H), 3.99 (m, 4H), 4.62 (s, 1,3-thiazol-4- 2H), 5.71 (s, 2H),6.90 (d, 2H), yl)phenoxy]pentoxy- 6.94 (d, 2H), 7.26 (m, 1H), 7.31 (m,benzamidine 4H), 7.50 (d, 2H), 7.57 (d, 2H), 9.44 (s, 1H) 128N-hydroxy-4-5-[4- propionylchloride thiourea bromoethanol 1.57 (m, 2H),1.80 (m, 4H), 2.24 (s, DMSO-d₆ (2-(bis-(2- 3H), 3.0-4.5 (brs, 2H), 3.67(s, hydroxyethyl)- 8H), 4.05 (m, 4H), 5.72 (s, 2H), amino)-5-methyl-7.03 (d, 2H), 7.12 (d, 2H), 7.44 (d, 1,3-thiazol-4- 2H), 7.82 (d, 2H)9.45 (s, 1H) yl)phenoxy]pentoxy- benzamidine 129 N-hydroxy-4-5-[4-butrylchloride thiourea bromoethanol 1.17 (t, 3H), 1.57 (m, 2H), DMSO-d₆(5-ethyl-2-((2- 1.78 (brm, 4H), 2.72 (q, 2H), hydroxyethyl)- 3.03 (s,3H), 3.45 (t, 2H), 3.59 (m, methyl-amino)-1,3- 2H), 4.01 (m, 4H) 4.79(t, 1H), thiazol-4- 5.70 (s, 2H) 6.90 (d, 2H), 6.96 (d,yl)phenoxy]pentoxy- 2H), 7.42 (d, 2H) 7.57 (d, 2H), benzamidine 9.43 (s,1H) 130 N-hydroxy-4-5-[4- butrylchloride thiourea bromoethanol 1.15 (m,6H), 1.56 (brm, 2H), DMSO-d₆ (5-ethyl-2-(ethyl- 1.76 (brm, 4H), 2.71 (q,2H), (2-hydroxyethyl)- 3.43 (m, 4H), 4.00 (t, 4H), 4.81 (t, amino)-1,3-1H), 5.70 (s, 2H) 6.90 (d, 2H), thiazol-4- 6.94 (d, 2H) 7.42 (d, 2H),7.81 (d, yl)phenoxy]pentoxy- 2H), 9.43 (s, 1H) benzamidine 131N-hydroxy-4-5-[4- butrylchloride thiourea chloroethyl- 1.17 (t, 3H) 1.56(m, 2H), 1.77 (m, DMSO-d₆ (5-ethyl-2- morpholine 4H), 2.41 (brm, 4H)2.51 (m, 2H), (methyl-(2- 2.72 (q, 2H), 3.00 (s, 3H), morpholinoethyl)-3.53 (brm, 6H), 3.99 (t, 4H), amino)-1,3- 5.70 (s, 2H) 6.90 (d, 2H),6.94 (d, thiazol-4- 2H), 7.42 (d, 2H) 7.57 (d, 2H), yl)phenoxy]pentoxy-9.43 (s, 1H) benzamidine 132 N-hydroxy-4-5-[4- butrylchloride thioureachloroethyl- 1.15 (m, 6H), 1.56 (m, 2H), DMSO-d₆ (5-ethyl-2-(ethyl-morpholine 1.78 (brm, 4H), 2.42 (brm, 4H), (2- 2.51 (m, 2H), 2.70 (q,2H), 3.40 (m, morpholinoethyl)- 2H), 3.48 (m, 2H) 3.53 (brm, 4H),amino)-1,3- 4.00 (m, 4H) 5.70 (s, 2H), 6.90 (d, thiazol-4- 2H), 6.94 (d,2H) 7.42 (d, 2H), yl)phenoxy]pentoxy- 7.57 (d, 2H) 9.43 (s, 1H)benzamidine 133 N-hydroxy-4-5-[4- butrylchloride thiourea benzyl 1.17(t, 3H), 1.57 (brm, 2H), DMSO-d₆ (2-(benzyl-methyl- bromide 1.77 (brm,4H), 2.74 (q, 2H), amino)-5-ethyl- 2.98 (s, 3H), 3.99 (m, 4H), 4.64 (s,1,3-thiazol-4- 2H), 5.71 (s, 2H), 6.90 (d, 2H), yl)phenoxypentoxy]- 6.94(d, 2H), 7.30 (m, 5H), 7.45 (d, benzamidine 2H), 7.57 (d, 2H), 9.44 (s,1H) 134 N-hydroxy-4-5-[4- butrylchloride thiourea 3-bromomethyl- 1.18(t, 3H), 1.56 (m, 2H), DMSO-d₆ (5-ethyl-2-(methyl- pyridin 1.77 (brm,4H), 2.74 (q, 2H), (pyridin-3-yl- 3.01 (s, 3H), 3.99 (t, 4H), 4.69 (s,methyl)amino)-1,3- 2H), 5.70 (s, 2H), 5.90 (d, 2H), thiazol-4- 6.95 (d,2H), 7.37 (m, 1H), 7.45 (d, yl)phenoxy]pentoxy- 2H), 7.57 (d, 2H), 7.72(d, 1H), benzamidine 8.47 (d, 1H), 8.55 (s, 1H), 9.43 (s, 1H) 135N-hydroxy-4-5-[4- butrylchloride thiourea benzyl 1.15 (m, 6H), 1.56 (m,2H), DMSO-d₆ (2-(benzyl-ethyl- bromide 1.76 (brm, 4H), 2.73 (q, 2H),amino)-5-ethyl-1,3- 3.41 (q, 2H), 3.99 (t, 4H), 4.63 (s, thiazol-4- 2H),5.70 (s, 2H), 6.90 (d, 2H), yl)phenoxy]pentoxy- 6.94 (d, 2H), 7.25 (m,1H), 7.32 (m, benzamidine 4H), 7.44 (d, 2H), 7.57 (d, 2H), 9.43 (s, 1H)136 N-hydroxy-4-5-[4- butrylchloride thiourea 3-bromomethyl- 1.15 (m,6H), 1.56 (m, 2H), 1.76 (m, DMSO-d₆ (5-ethyl-2-(ethyl- pyridin 4H), 2.73(q, 2H), 3.44 (q, 2H), (pyridin-3-yl- 3.99 (t, 4H), 4.66 (s, 2H), 5.70(s, methyl)amino)-1,3- 2H), 5.74 (s, 1H), 6.90 (d, 2H), thiazol-4- 6.94(d, 2H), 7.36 (m, 1H), 7.43 (d, yl)phenoxy]pentoxy- 2H), 7.57 (d, 2H),7.73 (d, 2H), benzamidine 8.46 (d, 1H), 8.56 (d, 1H), 9.44 (s, 1H) 137N-hydroxy-4-5-[4- butrylchloride thiourea 3-bromomethyl- 1.15 (t, 3H),1.56 (brm, 2H), DMSO-d₆ (2-(bis-(pyridin-3- pyridin 1.79 (brm, 4H), 2.73(q, 2H), yl-methyl)amino)-5- 3.99 (t, 2H), 4.09 (t, 2H), 4.91 (s,ethyl-1,3-thiazol- 4H), 6.95 (d, 2H), 7.14 (d, 2H), 4- 7.41 (d, 2H),7.67 (d, 2H), 7.82 (m, yl)phenoxy]pentoxy- 2H), 8.26 (m, 2H), 8.73 (m,2H), benzamidine 8.79 (s, 2H). 138 N-hydroxy-4-5-[4- butrylchloridethiourea propylbromide 0.86 (t, 6H), 1.17 (t, 3H), DMSO-d₆(2-dipropylamino-5- 1.59 (brm, 6H), 1.77 (brm, 4H), ethyl-1,3-thiazol-2.71 (q, 2H), 3.30 (m, 4H), 3.99 (m, 4- 4H), 5.71 (brs, 2H), 6.91 (d,2H), yl)phenoxy]pentoxy- 6.94 (d, 2H), 7.42 (d, 2H), 7.57 (d,benzamidine 2H), 9.44 (s, 1H) 139 N-hydroxy-4-5-[4- butrylchloridethiourea bromoethanol 1.17 (t, 3H), 1.57 (brm, 2H), DMSO-d₆ (2-(bis-(2-1.77 (brm, 4H), 2.71 (q, 2H), hydroxyethyl)amino)- 3.48 (m, 4H), 3.63(m, 4H), 3.99 (m, 5-ethyl-1,3- 4H), 4.87 (t, 2H), 5.69 (s, 2H),thiazol-4- 6.90 (d, 2H), 6.94 (d, 2H), 7.41 (d, yl)phenoxy]pentoxy- 2H),7.57 (d, 2H), 9.43 (s, 1H) benzamidine 140 N-hydroxy-4-5-[4-isovalerylchloride thiourea bromoethanol 1.26 (d, 6H), 1.57 (m, 2H),1.79 (m, DMSO-d₆ (2-((2- 4H), 3.33 (m, 5H), 3.47 (m, 1H), hydroxyethyl)-3.61 (m, 2H), 4.00 (m, 4H), 5.72 (s, methyl-amino)-5- 2H), 6.90-7.00 (b,4H), 7.45 (d, isopropyl-1,3- 2H), 7.57 (d, 2H), 9.45 (s, 1H) thiazol-4-yl)phenoxy]pentoxy- benzamidine 141 N-hydroxy-4-5-[4- isovalerylchloridethiourea 3-bromomethyl- 1.20 (d, 6H), 1.56 (m, 2H), 1.79 (m, DMSO-d₆(5-isopropyl-2- pyridin 4H), 3.01 (s, 3H), 3.24 (m, 1H),(methyl-(pyridin-3- 3.32 (s, 2H), 4.00 (m, 4H), 5.70 (s,ylmethyl)amino)- 2H), 6.90 (b, 4H), 7.40 (b, 3H), 1,3-thiazol-4- 7.57(d, 2H), 7.92 (m, 1H), yl)phenoxy]pentoxy- 8.47-8.56 (b, 2H), 9.43 (s,1H) benzamidine 142 N-hydroxy-4-5-[4- isovalerylchloride thioureaethansulfonyl- 1.24 (m, 9H), 1.56 (brm, 2H), DMSO-d₆ (2-(ethansulfonyl-chloride 1.79 (brm, 4H), 3.41 (s, 3H), 3.46 (q, methyl-amino)-5- 2H),4.00 (m, 4H), 5.74 (s, 2H), isopropyl-1,3- 6.91 (d, 2H), 6.95 (d, 2H),7.45 (d, thiazol-4- 2H), 7.57 (d, 2H), 9.45 (s, 1H) yl)phenoxy]pentoxy-benzamidine 143 N-hydroxy-4-5-[4- hexanoylchloride thiourea bromoethanol0.84 (t, 3H), 1.32 (m, 2H), 1.54 (m, DMSO-d₆ (5-butyl-2-((2- 4H), 1.78(m, 4H), 2.70 (t, 2H), hydroxyethyl)- 3.303 (s, 3H), 3.46 (t, 2H), 3.54(m, methyl-amino)-1,3- 2H), 4.01 (m, 4H), 5.71 (s, 2H), thiazol-4- 6.91(d, 2H), 6.94 (d, 2H), 7.42 (d, yl)phenoxy]pentoxy- 2H), 7.58 (d, 2H),9.46 (s, 1H) benzamidine 144 N-hydroxy-4-5-[4- hexanoylchloride thioureachloroethyl- 0.83 (t, 3H), 1.30 (m, 2H), 1.53 (m, DMSO-d₆(5-butyl-2-(methyl- morpholine 4H), 1.77 (brm, 4H), 2.42 (brm, 4H), (2-2.52 (m, 2H), 2.69 (m, 2H), 2.99 (s, morpholinoethyl)amino)- 3H, 3.52(brm, 6H), 4.00 (m, 4H), 1,3-thiazol-4- 5.72 (s, 2H), 6.92 (m, 4H), 7.41(d, yl)phenoxy]pentoxy- 2H), 7.57 (d, 2H), 9.44 (s, 1H) benzamidine 145N-hydroxy-4-5-[4- hexanoylchloride thiourea 3-bromomethyl- 0.82 (t, 3H),1.29 (m, 2H), 1.52 (brm, DMSO-d₆ (5-butyl-2-(methyl- pyridin 4H), 1.76(brm, 4H), 2.70 (m, 2H), (pyridin-3-yl- 3.00 (s, 3H), 3.98 (m, 4H), 4.68(s, methyl)amino)-1,3- 2H), 5.76 (s, 2H), 6.90 (d, 2H), thiazol-4- 6.94(d, 2H), 7.37 (m, 1H), 7.44 (d, yl)phenoxy]pentoxy- 2H), 7.58 (d, 2H),7.72 (d, 1H), benzamidine 8.47 (d, 1H), 8.55 (s, 1H), 9.48 (s, 1H) 146N-hydroxy-4-5-[4- hexanoylchloride thiourea propylbromide 0.84 (m, 9H),1.30 (m, 2H), 1.57 (m, DMSO-d₆ (5-butyl-2- 8H), 1.77 (brm, 4H), 2.68 (m,2H), dipropylamino-1,3- 3.33 (m, 4H), 4.00 (m, 4H), 5.70 (s, thiazol-4-2H), 6.90 (d, 2H), 6.94 (d, 2H), yl)phenoxyl]pentoxy- 7.41 (d, 2H), 7.57(d, 2H), 9.43 (s, benzamidine 1H) 147 N-hydroxy-4-5-[4- cyclopentyl-thiourea 3-bromomethyl- 1.10 (m, 2H), 1.51 (m, 6H), 1.76 (brm, DMSO-d₆(5- propionylchloride pyridin 6H), 1.99 (m, 1H), 2.71 (d, 2H),cyclopentylmethyl- 3.00 (s, 3H), 3.99 (t, 4H), 4.68 (s,2-(methyl-(pyridin- 2H), 5.72 (s, 2H), 6.90 (d, 2H), 3-yl-methyl)amino)-6.95 (d, 2H), 7.36 (m, 1H), 7.43 (d, 1,3-thiazol-4- 2H), 7.57 (d, 2H),7.72 (d, 1H), yl)phenoxy]pentoxy- 8.48 (d, 1H), 8.55 (s, 1H), 9.45 (s,benzamidine 1H) 148 N-hydroxy-4-5-[4- cyclopentyl- thiourea chloroethyl-1.11 (brm, 2H), 1.52-1.56 (brm, 6H), DMSO-d₆ (5- propionylchloridemorpholine 1.77 (brm, 6H), 2.0 (m, 1H), 2.69 (m, cyclopentylmethyl- 2H),3.00 (s, 3H), 3.33 (m, 4H), 2-(methyl-(2- 3.55 (m, 6H), 4.00 (m, 4H),5.81 (s, morpholinoethyl)amino)- 2H), 6.93 (m, 4H), 7.40 (d, 2H),1,3-thiazol-4- 7.57 (d, 2H), 9.50 (s, 1H) yl)phenoxy]pentoxy-benzamidine 149 N-hydroxy-4-5-[4- cyclopentyl- thiourea propylbromide0.85 (m, 6H), 1.08 (m, 2H), DMSO-d₆ (5- propionylchloride 1.46-1.77(brm, 16H), 1.99 (m, 1H), 2.67 (d, cyclopentylmethyl- 2H), 3.30 (m, 4H),3.99 (m, 4H), 2-dipropylamino- 6.04 (s, 2H), 6.90 (d, 2H), 6.93 (d,1,3-thiazol-4- 2H), 7.41 (d, 2H), 7.59 (d, 2H), yl)phenoxy]pentoxy- 9.60(s, 1H) benzamidine 150 N-hydroxy-4-5-[4- hexanoylchloride thioureaiodoethane 0.84 (m, 3H), 1.14 (t, 6H), 1.30 (m, DMSO-d₆ (5-butyl-2- 2H),1.55 (m, 4H), 1.77 (m, 4H), diethylamino-1,3- 2.69 (m, 2H), 3.40 (m,4H), 3.98 (m, thiazol-4- 4H), 5.73 (s, 2H), 6.92 (d-d, 4H),yl)phenoxy]pentoxy- 7.43 (d, 2H), 7.60 (d, 2H), 9.49 (s, benzamidine 1H)151 N-hydroxy-4-5-[4- hexanoylchloride thiourea iodoethane 0.85 (t, 3H),1.12 (t, 3H), 1.30 (m, DMSO-d₆ (5-butyl-2- 2H), 1.53 (m, 4H), 1.78 (m,4H), ethylmethylamino- 2.70 (m, 2H), 2.96 (s, 3H), 3.42 (m,1,3-thiazol-4- 2H), 5.74 (s, 2H), 6.93 (m, 4H), yl)phenoxy]pentoxy-7.43d, 2H), 7.59 (d, 2H), 9.47 (s, 1H) benzamidine 152 N-hydroxy-4-5-[4-hexanoylchloride thiourea iodomethane 0.81 (t, 3H), 1.25 (m, 2H), 1.52(m, DMSO-d₆ (5-butyl-2- 4H), 1.76 (m, 4H), 2.67 (m, 2H),dimethylamino-1,3- 2.97 (s, 6H), 3.97 (m, 4H), 5.70 (s, thiazol-4- 2H),6.91 (d-d, 4H), 7.41 (d, 2H), yl)phenoxy]pentoxy- 7.57 (d, 2H), 9.50 (s,1H) benzamidine 153 N-hydroxy-4-[5-(4- cyclopentyl- thioureachloroethyl- 1.56-1.59 (m, 6H), 1.73-1.81 (m, 6H), DMSO-d₆5-cyclopentyl-2- ethylchloride morpholine 2.00-2.10 (m, 2H), 2.38-2.49(m, 4H), [methyl-(2- 2.50-2.51 (m, 2H), 3.01 (s, 3H),morpholinoethyl)amino]- 3.25 (m, 1H), 3.52--3.55 (m, 6H), 1,3-thiazol-4.00-4.03 (m, 4H), 5.74 (s, 2H), 4- 6.91-6.97 (m, 4H), 7.41 (d, 2H),7.59 (d, ylphenoxy)pentoxy]- 2H), 9.47 (s, 1H) benzamidine 154N-hydroxy-4-[5-(4- isocaproylchloride thiourea chloroethyl- 0.88 (d,6H), 1.78 (m, 2H), DMSO-d₆ 5-isobutyl-2- morpholine 1.80-1.82 (m, 5H),2.43 (s, 3H), 2.50 (m, [methyl-(2- 2H), 2.53 (m, 2H), 3.01 (m, 2H),morpholinoethyl)amino]- 3.18 (m, 2H), 3.54 (m, 6H), 4.02 (m,1,3-thiazol- 4H), 5.76 (s, 2H), 6.94-6.97 (m, 4- 4H), 7.41 (d, 2H), 7.60(d, 2H), ylphenoxy)pentoxy]- 9.46 (s, 1H) benzamidine 155N-hydroxy-4-5-[4- 4- thiourea iodomethane 1.58-1.66 (m, 2H), 1.78-1.81(m, 4H) DMSO-d₆ (5-(2- chlorobutrylchloride 3.14 (s, 6H), 3.15 (t, 2H),3.81 (t, chloroethyl)-2- 2H), 4.02 (m, 4H), 5.72 (s, 2H),dimethylamino-1,3- 6.91-6.98 (m, 4H), 7.46 (d, 2H), 7.59 (d, thiazol-4-2H), 9.45 (s, 1H) yl)phenoxy]pentoxy- benzamidine 156 N-hydroxy-4-5-[4-cyclopentyl- thiourea propylbromide 0.86-0.88 (m, 6H), 1.58-1.61 (m,10H), DMSO-d₆ (5-cyclopentyl-2- ethylchloride 1.78 (m, 8H), 3.32-3.39(m, 5H), diethylamino-1,3- 4.02-4.05 (m, 4H), 6.95-7.18 (m, 4H),thiazol-4- 7.40 (d, 2H), 7.83 (d, 2H) yl)phenoxy]pentoxy- benzamidine157 N-hydroxy-4-5-[4- isovalerylchloride thiourea propylbromide0.84-0.88 (m, 6H), 1.24 (d, 6H), DMSO-d₆ [5-isopropyl-2- 1.57-1.63 (m,6H), 1.77-1.79 (m, 4H), dipropylamino-1,3- 3.28-3.38 (m, 5H), 3.97-4.01(m, 4H), thiazol-4- 5.71 (s, 2H), 6.89-6.95 (m, 4H), yl)phenoxy]pentoxy-7.41-4.59 (m, 4H), 9.45 (s, 1H) benzamidine 158 N-hydroxy-4-5-[4-butrylchloride thiourea ethylbromide 1.15 (t, 3H), 1.23 (t, 6H), DMSO-d₆(5-ethyl-2- 1.58 (m, 2H), 1.79-1.83 (m, diethylamino-1,3- 4H), 2.51 (m,2H), thiazol-4- 3.60-3.64 (m, 4H), 4.08-4.12 (m, yl)phenoxy]pentoxy-4H), 7.13-7.16 (m, 4H), benzamidine 7.43 (d, 2H), 7.69 (d, 2H) 158N-hydroxy-4-[5-(4- isovalerylchloride thiourea chloroethyl- 1.22 (d,6H), 1.56 (m 2H), DMSO-d₆ 5-isopropyl-2- morpholine 1.78 (m, 4H), 2.43(m, 4H), [methyl-(2- 2.55 (t, 2H), 3.05 (s, 3H), morpholinoethyl)amino]-3.34 (m, 1H), 3.51 (m, 4H), 1,3-thiazol-4- 3.61 (t, 2H), 3.99 (m, 4H),ylphenoxy)pentoxy]- 5.70 (brs, 2H), 6.90 (m, 4H), benzamidine 7.57 (m,2H), 7.73 (m, 2H), 9.44 (brs, 1H) 160 N-hydroxy-4-5-[4- cyclopentyl-thiourea iodoethane 1.12-1.16 (m, 8H), 1.56 (m, DMSO-d₆ (5-propionylchloride 6H), 1.78 (m, 6H), 1.98-2.00 (m, cyclopentylmethyl-1H), 2.68 (d, 2H), 2-diethylamino-1,3- 3.38-3.40 (m, 4H), 4.00 (m, 4H),thiazol-4- 5.89 (s, 2H), 6.91-6.95 (d-d, yl)phenoxy]pentoxy- 4H), 7.42(d, 2H), 7.59 (d, benzamidine 2H), 9.53 (s, 1H) 161 N-hydroxy-4-5-[4-isovalerylchloride thiourea iodomethane 1.20 (d, 6H), 1.56 (m, 2H),DMSO-d₆ (5-isopropyl-2- 1.78 (m, 4H), 2.98 (s, 6H), dimethylamino-1,3-3.34 (m, 1H), 3.98-4.01 (m, thiazol-4- 4H), 5.77 (s, 2H),yl)phenoxy]pentoxy- 6.90-6.96 (m, 4H), 7.39 (d, 2H), benzamidine 7.58(d, 2H), 9.47 (s, 1H) 162 N-hydroxy-4-5-[4- isovalerylchloride thioureaiodoethane 1.14 (m, 6H), 1.20 (d, 6H), DMSO-d₆ (5-isopropyl-2- 1.56 (m,2H), 1.78 (m, 4H), diethylamino-1,3- 3.30 (m, 1H), 3.40 (m, 4H),thiazol-4- 5.84 (s, 2H), 6.91-7.59 (m, yl)phenoxy]pentoxy- 8H), 9.51 (s,1H) benzamidine 163 N-hydroxy-4-5-[4- cyclopentyl- thiourea iodomethane1.10-1.18 (m, 2H), DMSO-d₆ (5- propionylchloride 1.44-1.57 (m, 6H),1.70-1.79 (m, cyclopentylmethyl- 6H), 1.98-2.01 (m, 1H),2-dimethylamino- 2.69 (d, 2H), 2.98 (s, 6H), 1,3-thiazol-4- 3.97-4.02(m, 4H), 5.77 (s, yl)phenoxy]pentoxy- 2H), 6.90-6.94 (d-d, 4H),benzamidine 7.42 (d, 2H), 7.59 (d, 2H), 9.48 (s, 1H)

Examples 164 to 176

Compound (20) prepared according to the same method as that in thePreparative Example 4 was reacted in the same manner as Example, 1,obtaining the title compounds shown I Table 5.

Table 5 shows the title compounds, reactants and ¹H-NMR data.

TABLE 5 Acid example name chloride Thioamide Alkylhalide NMR solvent mp164 N-hydroxy-4-5-[4- propionylchloride thiourea 1,5-dibromo- 1.56 (m,2H), 1.63 (brm, 6H), 1.78 (brm, DMSD-d₆ + TFA- (5-methyl-2- pentane 4H),3.60 (brm, 4H), 4.02 (t, 2H), d₁ piperidino-1,3- 4.06 (t, 2H), 7.04 (d,2H), 7.09 (d, 2H), thiazol-4- 7.40 (d, 2H), 7.66 (d, 2H)yl)phenoxy]pentoxy- benzamidine 165 N-hydroxy-4-5- propionylchloridethiourea bisdibromid- 1.56 (m, 2H), 1.78 (brm, 4H), 2.21 (s, DMSD-d₆ +TFA- [4-(5-methyl-2- ethylester 3H), 3.60 (brm, 4H), 3.74 (brm, 4H), d₁morpholine-1,3- 4.02 (t, 2H), 4.05 (t, 2H), 7.03 (d, 2H), thiazol-4-7.09 (d, 2H), 7.40 (d, 2H), 7.65 (d, 2H) yl)phenoxy]pentoxy- benzamidine166 N-hydroxy-4-5-[4- butrylchloride thiourea 1,5-dibromo- 1.09 (t, 3H),1.55 (m, 2H), 1.61 (brm, DMSD-d₆ + TFA- (5-ethyl-2- pentane 6H), 1.77(brm, 4H), 2.56 (q, 2H), d₁ piperidino-1,3- 3.59 (brm, 4H), 4.00 (t,2H), 4.03 (t, thiazol-4- 2H), 7.01 (d, 2H), 7.06 (d, 2H), 7.34 (d,yl)phenoxy]pentoxy- 2H), 7.64 (d, 2H) benzamidine 167 N-hydroxy-4-5-[4-cyclopentyl- thiourea 1,5-dibromo- 1.01 (brm, 2H), 1.43 (brm, 4H),DMSD-d₆ + TFA- (5- propionylchloride pentane 1.56 (brm, 2H), 1.63 (brm,8H), d₁ cyclopentylmethyl- 1.78 (brm, 4H), 1.94 (m, 1H), 2.56 (d,2-piperidino- 2H), 3.61 (brm, 4H), 4.05 (m, 4H), 1,3-thiazol-4- 7.04 (d,2H), 7.10 (d, 2H), 7.36 (d, 2H), yl)phenoxy]pentoxy- 7.66 (d, 2H)benzamidine 168 N-hydroxy-4-5-[4- cyclopentyl- thiourea bisdibromid-1.02 (brm, 2H), 1.43 (brm, 4H), DMSD-d₆ + TFA- (5- propionylchlorideethylester 1.56 (brm, 2H), 1.66 (brm, 2H), d₁ cyclopentylmethyl- 1.78(brm, 4H), 1.94 (m, 1H), 2.58 (d, 2-morpholino- 2H), 3.61 (brm, 4H),3.74 (brm, 4H), 1,3-thiazol-4- 4.05 (m, 4H), 7.04 (d, 2H), 7.09 (d, 2H),yl)phenoxy]pentoxy- 7.36 (d, 2H), 7.65 (d, 2H) benzamidine 169N-hydroxy-4-(5- isovaleryl- thiourea bisdibromid- 1.22 (d, 6H), 1.58 (m,2H), 1.78 (m, 4H), DMSO-d₆ [4-(5-isopropyl- chloride ethylester 3.26 (m,1H), 3.35 (m, 4H), 3.70 (m, 2-morpholin-4-yl- 4H), 4.02 (m, 4H), 5.71(brs, 2H), 1,3-thiazol-4- 6.95 (m, 4H), 7.40 (d, 2H), 7.58 (d,yl)phenoxy]pentoxy)- 2H), 9.44 (s, 1H) benzamidine 170 N-hydroxy-4-(5-4-cyclopentyl- thiourea mechlore- 1.11 (brm, 2H), 1.52-1.56 (brm, 6H),DMSO-d₆ [5- propionylchloride thamine 1.77 (brm, 6H), 2.00 (m, 1H), 2.50(m, cyclopentylmethyl- 2H), 2.69 (m, 2H), 3.00 (s, 3H), 2-(4- 3.33 (m,4H), 3.55 (m, 6H), 4.00 (m, methylpiperazino)- 4H), 5.81 (brs, 2H), 6.93(m, 4H), 1,3-thiazol-4- 7.40 (d, 2H), 7.57 (d, 2H), 9.50 (brs,yl]phenoxypentoxy)- 1H) benzamidine 171 N-hydroxy-4-(5- 4-chlorobutryl-thiourea bisdibromid- 1.55 (m, 2H), 1.79 (m, 4H), 3.17 (d, 1H), DMSO-d₆[4-(5-vinyl-2- chloride ethylether 3.35 (m, 4H), 3.42 (m, 2H), 3.72 (m,4H), morpholin-4-yl- 4.01 (m, 4H), 5.74 (s, 2H), 6.92 (m, 4H),1,3-thiazol-4- 7.60 (d, 2H), 7.77 (d, 2H), 9.45 (s, 1H)yl)phenoxy]pentoxy)- benzamidine 172 N-hydroxy-4-(5- cyclopentylethyl-thiourea bisdibromid- 1.58-1.60 (m, 7H), DMSO-d₆ [4-(5- chlorideethylether 1.74-1.81 (m, 7H), 2.51 (m, 4H), cyclopentyl-2- 3.34-3.36 (m,1H), morpholin-4-yl- 3.69-3.71 (m, 4H), 4.00-4.02 (m, 1,3-thiazol-4-4H), 5.77 (s, 2H), yl)phenoxy]pentoxy)- 6.92-6.98 (m, 4H), 7.42 (d, 2H),benzamidine 7.59 (d, 2H), 9.48 (s, 1H) 173 N-hydroxy-4-(5- isocaproyl-thiourea bisdibromid- 0.88 (d, 6H), 1.59 (m, 2H), DMSO-d₆[4-(5-isobutyl- chloride ethylether 1.80 (m, 4H), 2.60 (m, 1H),2-morpholin-4- 3.35 (m, 8H), 3.70 (m, 2H), yl-1,3-thiazol- 4.01 (m, 4H),5.77 (brs, 2H), 4- 6.94 (m, 4H), 7.44 (m, 2H), yl)phenoxy]pentoxy)- 7.59(m, 2H), 9.48 (brs, 1H) benzamidine 174 N-hydroxy-4-(5- butrylchloridethiourea mechlore- 1.19 (t, 3H), 1.50-1.59 (m, DMSO-d₆ 4-[5-ethyl-2-(4-thamine 2H), 1.80 (m, 4H), 2.21 (s, methylpiperazino)- 3H), 2.41 (m,4H), 3.36 (m, 1,3-thiazol-4- 6H), 4.01 (m, 4H), 5.71 (brs,yl]phenoxypentoxy)- 2H), 6.93-6.96 (m, 4H), benzamidine 7.44 (m, 2H),7.58 (m, 2H), 9.46 (brs, 1H) 175 N-hydroxy-4-(5- propionylchloridethiourea bisdibromid- 1.56 (m, 2H), 1.77 (m, 4H), DMSO-d₆[4-(2-morpholin- ethylether 3.42 (m, 8H), 3.98 (m, 4H), 4-yl-1,3- 5.73(brs, 2H), 6.81 (m, thiazol-4- 2H), 6.92 (m, 2H), 7.11 (s, 1H),yl)phenoxy]pentoxy)- 7.27 (m, 2H), 7.77 (m, 2H), benzamidine 8.35 (brs,1H) 176 N-hydroxy-4-(5- isovaleryl- thiourea mechlore- 1.23 (d, 6H),1.58 (m, 2H), DMSO-d₆ 4-[5-isopropyl- chloride thamine 1.77 (m, 4H),2.21 (s, 3H), 2-(4- 2.40 (m, 4H), 2.21 (s, 3H), methylpiperazino)- 2.40(m, 4H), 3.33 (m, 1H), 1,3-thiazol-4- 3.35 (m, 4H), 4.00 (m, 4H),yl]phenoxypentoxy)- 5.71 (s, 2H), 6.93-6.97 (m, benzamidine 4H), 7.40(d, 2H), 7.58 (d, 2H), 9.45 (s, 1H)

Examples 177 to 213

Compound (12) prepared according to the same method as that in thePreparative Example 1-6 was reacted in the same manner as Example 1,obtaining the title compounds shown I Table 6.

Table 6 shows the title compounds, reactants and ¹H-NMR data.

TABLE 6 Acid example name chloride Thioamide Alkylhalide NMR solvent mp177 N-hydroxy-4-(5-[4-(5- isovalerylchloride thioacetamide — 1.23 (d,6H), 1.52 (m, 2H), DMSO-d₆ isopropyl-2-methyl- 1.60 (m, 2H), 1.75 (m,2H), 1,3-thiazol-4-yl)- 2.60 (s, 3H), 3.03 (m, 2H), phenoxy]- 3.32 (m,1H), 4.00 (t, 2H), pentylamino)- 5.52 (s, 2H), 5.79 (m, 1H), benzamidine6.51 (d, 2H), 6.99 (d, 2H), 7.37 (d, 2H), 7.42 (d, 2H), 9.19 (s, 1H) 178N-hydroxy-4-2-[2-(4- ″ ″ — 1.25 (d, 6H), 2.64 (s, 3H), CDCl₃(5-isopropyl-2- 3.33 (m, 1H), 3.90 (m, 4H), methyl-1,3-thiazol-4- 4.14(m, 4H), 6.90 (m, 4H), yl)-phenoxy)-ethoxy]- 7.40 (m, 4H)ethoxy-benzamidine 179 N-hydroxy-4-(3- ″ ″ — 1.26 (d, 6H), 1.32 (s, 3H),CDCl₃ hydroxy-5-[4-(5- 2.06 (m, 4H), 2.65 (s, 3H), isopropyl-2-methyl-3.33 (m, 1H), 4.20 (m, 4H), 1,3-thiazol-4-yl)- 5.01 (brs, 1H), 6.86 (d,2H), phenoxy)-3-methyl- 6.92 (d, 2H), 7.43 (d, 2H), pentyloxy]- 7.50 (d,2H) benzamidine 180 N-hydroxy-4-(2-(2-[4- ″ ″ — 1.10 (d, 3H), 1.23 (d,6H), DMSO-d₆ (5-isopropyl-2- 2.59 (s, 3H), 2.96 (m, 2H),methyl-1,3-thiazol-4- 3.05 (m, 1H), 3.32 (m, 2H), yl)-phenoxy]-1- 3.90(m, 2H), 4.04 (m, 2H), methyl-ethylamino)- 5.71 (s, 2H), 6.92 (d, 2H),ethoxy)-benzamidine 6.99 (d, 2H), 7.43 (d, 2H), 7.58 (d, 2H), 9.45 (s,1H) 181 N-hydroxy-4-3-[4-(3- ″ ″ — 1.23 (d, 6H), 1.85 (m, 4H), DMSO-d₆(4-(5-isopropyl-2- 2.40 (brm, 12H), 2.45 (s, 3H), methyl-1,3-thiazol-4-3.30 (m, 1H), 4.00 (m, 4H), yl)-phenoxy)-propyl)- 5.70 (s, 2H), 6.89 (d,2H), piperazin-1-yl]- 6.94 (d, 2H), 7.41 (d, 2H), propoxy-benzamidine7.57 (d, 2H), 9.51 (s, 1H) 182 N-hydroxy-4-5-[4-(5- ″ ″ — 1.23 (d, 6H),1.77 (brs, 4H), DMSO-d₆ isopropyl-2-methyl- 2.40 (m, 2H), 2.60 (s, 3H),1,3-thiazol-4-yl)- 3.33 (m, 1H), 4.02 (brs, 2H), phenoxy]-pentanoyl-5.72 (s, 2H), 6.99 (d, 2H), amino-benzamidine 7.43 (d, 2H), 7.58-7.80(m, 4H), 9.51 (s, 1H), 10.00 (s, 1H) 183 N-hydroxy-4-5-[4-(5- ″ ″ — 1.22(d, 6H), 1.43 (m, 2H), DMSO-d₆ isopropyl-2-methyl- 1.55 (m, 2H), 1.76(m, 2H), 1,3-thiazol-4-yl)- 2.59 (s, 3H), 2.89 (s, 3H), phenoxy]-pentyl-3.33 (m, 1H), 3.98 (m, 2H), DMSO-d₆ methyl-amino- 5.55 (s, 2H), 6.64 (d,2H), benzamidine 6.97 (d, 2H), 7.45 (m, 4H), 9.23 (s, 1H) 184N-hydroxy-4-4-[4- isovalerylchloride thioacetamide — 1.23 (d, 6H), 2.60(s, 3H), DMSO-d₆ (5-isopropyl-2- 3.31 (m, 1H), 4.63 (brs, 4H),methyl-1,3-thiazol- 5.73 (s, 2H), 6.08 (brs, 2H), 4-yl)-phenoxy]-2- 6.94(d, 2H), 7.01 (d, 2H), butenyloxy- 7.44 (d, 2H), 7.58 (d, 2H),benzamidine 9.46 (s, 1H) 185 N-hydroxy-4-(4-[4- ″ ″ — 1.23 (d, 6H), 2.64(s, 3H), DMSO-d₆ (5-isopropyl-2- 3.32 (m, 1H), 5.15 (s, 2H),methyl-1,3-thiazol- 5.23 (s, 2H), 5.72 (s, 2H), 4-yl)- 7.07 (d, 2H),7.19 (d, 2H), phenoxymethyl]- 7.46 (m, 6H), 7.73 (d, 2H), benzyloxy)-9.46 (s, 1H) benzamidine 186 N-hydroxy-4-(2-(2- ″ ″ — 1.23 (d, 6H), 2.59(s, 3H), DMSO-d₆ [4-(5-isopropyl-2- 3.01 (brs, 4H), 3.33 (m, 1H),methyl-1,3-thiazol- 4.09 (m, 4H), 5.71 (s, 2H), 4-yl)phenoxy]- 6.92 (d,2H), 7.00 (d, 2H), ethylamino)- 7.43 (d, 2H), 7.58 (d, 2H),ethoxy)-benzamidine 9.45 (s, 1H) 187 N-hydroxy-2-fluoro- ″ ″ — 1.23 (d,6H), 1.57 (m, 2H), DMSO-d₆ 4-(5-[4-(5- 1.79 (m, 4H), 2.49 (s, 3H),isopropyl-2-methyl- 3.33 (m, 1H), 4.02 (m, 4H), 1,3-thiazol-4-yl)- 5.70(s, 2H), 6.83 (m, 2H), phenoxy]- 6.98 (d, 2H), 7.43 (m, 3H), pentyloxy)-9.51 (s, 1H) benzamidine 188 2,N-dihydroxy-4-(5- ″ ″ — 1.23 (d, 6H),1.56 (m, 2H), DMSO-d₆ [4-(5-isopropyl-2- 1.77 (m, 4H), 2.60 (s, 3H),methyl-1,3-thiazol- 3.32 (m, 1H), 4.00 (m, 4H), 4-yl)-phenoxy]- 6.25 (s,2H), 6.36 (m, 2H), pentyloxy)- 7.00 (d, 2H), 7.42 (d, 2H), benzamidine7.52 (d, 1H), 9.81 (s, 1H), 12.40 (s, 1H) 189 N-hydroxy-4-(5-[4- ″ ″ —1.24 (d, 6H), 1.58 (m, 2H), DMSO-d₆ (5-isopropyl-2- 1.80 (m, 4H), 2.61(s, 3H), methyl-1,3-thiazol- 3.35 (m, 1H), 3.77 (s, 3H) 4-yl)-phenoxy]-4.02 (m, 4H), 5.77 (s, 2H), pentyloxy)-3- 6.98 (m, 3H), 7.26 (m, 2H),methoxy-benzamidine 7.46 (d, 2H), 9.48 (s, 1H) 190 N-hydroxy-2- ″ ″ —1.23 (m, 12H), 1.54 (m, 2H), DMSO-d₆ cyclohexylamino-4- 1.65 (m, 2H),1.76 (m, 4H), (5-[4-(5-isopropyl- 1.78 (m, 2H), 2.60 (s, 3H),2-methyl-1,3- 3.34 (m, 2H), 3.99 (m, 4H), thiazol-4-yl)- 5.66 (s, 2H),6.09 (m, 2H), phenoxy]- 6.97 (d, 2H), 7.31 (d, 1H), pentyloxy)- 7.43 (d,2H), 7.70 (d, 1H), benzamidine 9.48 (s, 1H) 191 N-hydroxy-4-(5-[3- ″ ″ —1.17 (d, 6H), 1.57 (m, 2H), DMSO-d₆ fluoro-4-(5- 1.79 (brs, 4H), 2.98(m, 1H), isopropyl-2-methyl- 4.04 (m, 4H), 5.71 (s, 2H),1,3-thiazol-4-yl)- 6.90 (m, 3H), 7.31 (d, 2H), phenoxy]- 7.59 (d, 2H),9.44 (s, 1H) pentyloxy)- benzamidine 192 N-hydroxy-2-fluoro-isovalerylchloride thioacetamide — 1.17 (d, 6H), 1.57 (brs, 2H), DMSO-d₆4-(5-[3-fluoro-4- 1.79 (brs, 4H), 2.98 (m, 1H), (5-isopropyl-2- 4.05 (m,4H), 5.73 (s, 2H), methyl-1,3-thiazol- 6.82-6.89 (m, 4H), 7.27-7.40 (m,4-yl)-phenoxy]- 2H), 9.52 (s, 1H) pentyloxy)- benzamidine 193N-hydroxy-4-(3-[4- ″ ″ — 1.24 (d, 6H), 2.20 (m, 2H), DMSO-d₆(5-isopropyl-2- 2.60 (s, 3H), 3.30 (m, 1H), methyl-1,3-thiazol- 4.17 (m,4H), 5.71 (s, 2H), 4- 6.96 (d, 2H), 7.01 (d, 2H), yl)phenoxy]propoxy)-7.44 (d, 2H), 7.60 (d, 2H), benzamidine 9.45 (s, 1H) 194N-hydroxy-4-(4-[4- ″ ″ — 1.26 (d, 2H), 1.89 (m, 4H), DMSO-d₆(5-isopropyl-2- 2.60 (s, 3H), 3.30 (m, 1H), methyl-1,3-thiazol- 4.06 (m,4H), 5.72 (s, 2H), 4- 6.92 (d, 2H), 7.00 (d, 2H), yl)phenoxy]butoxy)-7.44 (d, 2H), 7.60 (d, 2H), benzamidine 9.45 (s, 1H) 195N-hydroxy-3-(5-[4- ″ ″ — 1.24 (d, 6H), 1.50-1.62 (m, 3H), DMSO-d₆(5-isopropyl-2- 1.77-1.79 (m, 2H), 2.65 (s, 3H), methyl-1,3-thiazol-3.02-3.04 (m, 1H), 3.37-3.44 (m, 4-yl)-phenoxy]- 3H), 3.99-4.03 (m, 2H),pentylamino)- 6.57-6.98 (m, 4H), 7.00 (d, 2H), benzamidine 7.44 (d, 2H)196 N-hydroxy-4-(4-[4- butrylchloride cyclohexan- — 1.22 (t, 3H),1.39-1.44 (m, 3H), DMSO-d₆ (2-cyclohexyl-5- carbothioic 1.59 (m, 1H),1.77 (m, 2H), ethyl-1,3-thiazol- acid amide 1.89 (m, 4H), 2.03 (m, 2H),4-yl)-phenoxy]- 2.90 (m, 3H), 4.18 (m, 4H), butoxy)-benzamidine 7.00 (m,4H), 7.49 (m, 2H), 7.60 (m, 2H) 197 N-hydroxy-4-[5-(4- ″ thioureabromoethanol 1.17 (m, 3H), 2.19 (m, 2H), DMSO-d₆ 5-ethyl-2-[(2- 2.72 (m,2H), 3.05 (s, 3H), hydroxyethyl)- 3.39-3.79 (m, 4H), 4.16-4.20 (m,methyl-amino]-1,3- 4H), 5.72 (s, 2H), 6.96 (m, 4H), thiazol-4-yl-7.40-7.84 (m, 4H), 9.47 (s, 1H) phenoxy)propoxy]- benzamidine 198N-hydroxy-4-[5-(4- ″ ″ ″ 1.15 (t, 3H), 1.90 (m, 4H), DMSO-d₆5-ethyl-2-[(2- 2.64 (q, 2H), 3.25 (s, 3H), hydroxyethyl)- 3.40-3.80 (m,4H), 4.10-4.15 (m, 4H), methyl-amino]-1,3- 7.09-7.15 (m, 4H), 7.42 (d,2H), thiazol-4-yl- 7.73 (d, 2H) phenoxy)butoxy]- benzamidine 199N-hydroxy-4-[5-(4- ″ thiourea 3-bromo- 1.86 (t, 3H), 2.50 (m, 2H),DMSO-d₆ 5-ethyl-2-[methyl- methylpyridin 2.73 (m, 2H), 3.15 (s, 3H),(pyridin-3-yl- 4.17-4.25 (m, 4H), 4.96 (s, 2H), methyl)amino]-1,3- 7.01(d, 2H), 7.17 (d, 2H), thiazol-4-yl- 7.44 (d, 2H), 7.73 (d, 2H),phenoxy)propoxy]- 8.06 (m, 1H), 8.54 (d, 1H), benzamidine 8.87 (d, 1H),8.94 (s, 1H) 200 N-hydroxy-4-[5-(4-5-ethyl- ″ ″ 3-bromo- 1.19 (t, 3H),1.79-1.89 (m, DMSO-d₆ 2-[methyl-(pyridin-3-yl- methylpyridin 4H),2.72-2.74 (m, 2H), methyl)amino]-1,3-thiazol- 3.17 (s, 3H), 4.07-4.15(m, 4-yl-phenoxy)butoxy]- 4H), 4.98 (s, 2H), 7.00 (d, benzamidine 2H),7.14 (d, 2H), 7.44 (d, 2H), 7.72 (d, 2H), 8.05 (m, 1H), 8.55 (d, 1H),8.87(d, 1H), 8.95 (s, 1H) 201 N-hydroxy-4-(4-[4-(5- cyclopentyl-thioisobutryl- — 1.14 (m, 2H), 1.32 (d, 6H), DMSO-d₆cyclopentylmethyl-2- propionylchloride amide 1.48 (m, 4H), 1.74 (m, 2H),isopropyl-1,3-thiazol-4- 2.04 (m, 1H), 2.85 (d, 2H), yl)-phenoxymethyl]-3.38 (m, 1H), 5.14 (s, 4H), benzyloxy)-benzamidine 5.73 (s, 2H), 7.01(d, 2H), 7.08 (d, 2H), 7.48 (s, 4H), 7.50 (d, 2H), 7.58 (d, 2H), 9.48(s, 1H) 202 N-hydroxy-4-(4-[4-(5- hexanoylchloride thioisobutryl- — 0.85(t, 3H), 1.32 (d, 6H), DMSO-d₆ butyl-2-isopropyl-1,3- amide 1.35 (m,2H), 1.60 (m, 2H), thiazol-4-yl)- 1.85 (m, 2H), 3.25 (m, 1H),phenoxymethyl]-benzyloxy)- 5.15 (s, 4H), 5.74 (s, 2H), benzamidine 7.01(d, 2H), 7.08 (d, 2H), 7.48 (s, 4H), 7.50 (d, 2H), 7.60 (d, 2H), 9.49(s, 1H) 203 N-hydroxy-4-(4-[4-(5- cyclopentyl- thiourea — 1.07-1.09 (m,2H), DMSO-d₆ cyclopentylmethyl-2-amino- propionylchloride 1.47-1.50 (m,4H), 1.70 (m, 2H), 1,3-thiazol-4-yl)- 1.99 (m, 1H), 2.34 (s, 6H),phenoxymethyl]-benzyloxy)- 2.62 (d, 2H), 5.18 (s, 2H), benzamidine 5.25(s, 2H), 7.17-7.24 (m, 4H), 7.41 (d, 2H), 7.50 (m, 4H), 7.68 (d, 2H) 204N-hydroxy-4-(4-[4-(5- cyclopentyl- ″ — 1.05 (m, 2H), 1.49 (m, 4H),DMSO-d₆ cyclopentylmethyl-2-amino- propionylchloride 1.71 (m, 2H), 2.00(m, 1H), 1,3-thiazol-4-yl)- 2.34 (s, 6H), 2.63 (d, 2H),phenoxymethyl]-benzyloxy)- 5.15-5.26 (d, 4H), 2-fluoro-benzamidine7.05-7.24 (m, 3H), 7.41-7.62 (m, 8H) 205 N-hydroxy-4-(4-[4-(2-acetylchloride ″ iodomethane 2.86 (s, 3H), 5.16 (m, 4H), DMSO-d₆methylamino-1,3-thiazol-4- 6.00 (brs, 2H), 7.02 (m, 4H),yl)-phenoxymethyl]- 7.48 (m, 4H), 7.60 (s, 1H), benzyloxy)-benzamidine7.76 (m, 4H), 9.57 (brs, 1H) 206 N-hydroxy-4-(6-[4-(5-isovalerylchloride thioacetamide — 1.26 (d, 6H), 2.61 (s, 3H), DMSO-d₆isopropyl-2-methyl-1,3- 3.35 (m, 1H), 5.25 (m, 4H), thiazol-4-yl)- 5.75(brs, 2H), 7.11 (m, 1H), phenoxymethyl]-pyridin-2- 7.13 (m, 2H), 7.47(m, 4H), yl-methoxy)-benzamidine 7.49 (m, 2H), 7.80-7.90 (m, 2H), 9.49(brs, 1H) 207 N-hydroxy-2-fluoro-4-(5- ″ ″ — 1.25 (d, 6H), 1.89 (m, 4H),DMSO-d₆ [4-(5-isopropyl-2-methyl- 2.61 (s, 3H), 3.34 (m, 1H),1,3-thiazol-4-yl)- 4.10 (m, 4H), 6.80-6.90 (m, phenoxy]-butoxy)- 2H),7.02 (m, 2H), 7.46 (m, 3H) benzamidine 208 N-hydroxy-4-(2-[4-(5- ″ ″ —1.23 (d, 6H), 2.60 (s, 3H), DMSO-d₆ isopropyl-2-methyl-1,3- 3.33 (m,1H), 5.28 (s, 4H), thiazol-4-yl)- 5.80 (s, 2H), 7.04-7.12 (m,phenoxymethyl]- 4H), 7.37 (m, 2H), 7.47 (d, benzyloxy)-benzamidine 2H),7.55 (m, 2H), 7.64 (d, 2H), 9.57 (s, 1H) 209 N-hydroxy-4-(3-[4-(5- ″ ″ —1.23 (d, 6H), 2.60 (s, 3H), DMSO-d₆ isopropyl-2-methyl-1,3- 3.31 (m,1H), 5.14 (s, 2H), thiazol-4-yl)- 5.15 (s, 2H), 5.72 (s, 2H),phenoxymethyl]- 7.00 (d, 2H), 7.08 (d, 2H), benzyloxy)-benzamidine7.42-7.46 (m, 5H), 7.55-7.61 (m, 3H), 9.46 (s, 1H) 210N-hydroxy-4-(4-[4-(5- cyclopentyl- cyclohexan- — 1.10 (m, 2H), 1.23 (m,1H), DMSO-d₆ cyclopentylmethyl-2- propionylchloride carbothioic 1.46(br, 9H), 1.77 (br, 4H), cyclohexyl-1,3-thiazol- acid amide 2.02 (m,3H), 2.83 (d, 2H), 4-yl)-phenoxymethyl]- 2.90 (m, 1H), 5.16 (m, 4H),benzyloxy)-benzamidine 5.81 (brs, 2H), 7.02 (m, 4H), 7.48 (m, 4H), 7.76(m, 4H), 9.57 (brs, 1H) 211 N-hydroxy-4-(6-[4-(5- isovalerylchloridethioacetamide — 1.24 (d, 6H), 1.49 (m, 4H), DMSO-d₆isopropyl-2-methyl-1,3- 1.76 (m, 4H), 2.61 (s, 3H),thiazol-4-yl)phenoxy]- 3.32-3.37 (m, 1H), hexyloxy)-benzamidine3.99-4.02 (m, 4H), 5.81 (s, 2H), 6.91 (d, 2H), 6.99 (d, 2H), 7.44 (d,2H), 7.59 (d, 2H), 9.49 (s, 1H) 212 N-hydroxy-4-(5-[2-ethyl-butrylchloride ″ — 1.13 (t, 3H), 1.61 (m, 2H), DMSO-d₆5-hydroxy-4-(2-methyl- 1.81 (m, 4H), 2.51 (m, 2H), 1,3-thiazol-4- 2.79(s, 3H), 3.97-4.10 (m, yl)phenoxy]-pentyloxy)- 4H), 6.60 (s, 1H), 7.12(d, benzamidine 2H), 7.69-7.86 (m, 4H), 8.81 (s, 1H), 9.26 (s, 1H) 213N-hydroxy-4-(5-[2-ethyl- butrylchloride thioacetamide — 1.03 (t, 3H),1.13 (t, 3H), DMSO-d₆ 4-(2-methyl-1,3-thiazol- 1.62 (m, 2H), 1.79-1.85(m, 4-yl)-5-propoxy- 6H), 2.55 (m, 2H), 2.69 (s, phenoxy]-pentyloxy)-3H), 4.01-4.08 (m, 6H), benzamidine 5.73 (s, 2H), 6.67 (s, 1H), 6.92 (d,2H), 7.59-7.93 (m, 4H), 9.47 (s, 1H)

Experimental Example 1 Inhibitory Effects on Osteoclast Differentiation

The effect of benzamidine derivatives of the present invention onosteoclast proliferation and differentiation process was evaluated viaco-culture with osteoblast.

1-1. Preparation of Cells a) Preparation of Bone Marrow Cells

Tibia and Femora were aseptically ectomized from male ddY mice of 6-8weeks to harvest bone marrow cells by using a syringe (21G, Korea GreenCross).

The bone marrow cells were suspended in 5 mL α-MEM medium (Gibco BRLCo.) containing sodium bicarbonate (2.0 g/L), streptomycin (100 mg/L)and penicillin (100,000 unit/mL). The harvested cells were centrifugedat 600×g for 5 mins to collect the whole quantity. To remove the redblood cells within bone marrow cells, 3 mL of Tris HCl (0.83% NH₄Cl,pH7.5) was added and well mixed. After centrifuging above cells, thenumbers of bone marrow cells were counted and then, the bone marrowcells were immediately used for co-culture system with osteoblast.

b) Preparation of Osteoblast

The calvaria were aseptically ectomized from neonate ICR mice of 1˜2days, washed with PBS solution and incubated with a mixture of enzymesolution (0.2% collagenase and 0.1% dispase) at 37° C. gentle shaker.This procedure was sequentially repeated (10, 10, 10, 20, 20 and 20mins), and then the calvaria cells having the characteristics ofosteoblast mostly released from III-VI digestion groups were collectedand washed with the medium (serum-free α-MEM). The washed cells werecultivated in α-MEM medium containing 10% FBS for 2˜3 days. Aftersubculturing, these cells were used for this experiment, and diluted toreach the concentration of 1×10⁶ cell/mL for storage at −70° C.

1-2. Measurement of Osteoclast Differentiation a) Preparation ofSpecimen

Benzamidine derivatives of the present invention were dissolved in asterile distilled water or ethanol to make desired concentrationsfollowing dilution. The final volume of specimen added to the medium wasdetermined at the ratio of 1:1000.

b) Reaction with Specimens Via Co-Culture System

Bone marrow cells prepared, in the above and osteoblast from calvariawere co-cultured for osteoclast differentiation. Both bone marrow cells(25,000 cells/cm²) and osteoblast (10,000 cells/cm²) were plated on a 96well plate in α-MEM medium containing FBS with specimen, and thencultured with test materials for 7 days. Differentiation factors, suchas dexamethasone (10⁻⁷M) and vitamin D₃ (10⁻⁸M), were also continuouslyadded to the medium from the first day of cultivation. The medium waschanged with fresh media containing a mixture of specimens anddifferentiation factors every 2˜3 day.

c) Evaluation of Osteoclast Differentiation 1) Preparation of TartarateResistance Acid Phosphatase (TRAP) Staining Solution

TRAP was used as a marker to measure osteoclast in consideration of itscharacteristics showing a positive reaction to TRAP staining solution.TRAP staining solution was prepared in a manner that 5 mg of naphtolAS-MS phosphate (sigma N-4875), a substrate and 25 mg of coloring agent(Fast Red Violet LB salt) were dissolved in N,N-dimethylformamide (about0.5 mL), 0.1N NaHCO₃ buffer solution (50 mL) containing 50 mM tartaricacid was added, and the reaction mixture was stored at refrigeratorprior to use.

2) Staining Method

After culturing the cells for 7 days, the medium was removed from thewells, the cells were once washed with PBS solution and fixed to PBScontaining 10% formalin for 2˜5 mins. The cells were fixed again in amixed solution of ethanol and acetone (1/1) for about 1 min, and driedoff. The cells were further treated by TRAP staining solution for 15mins and washed with PBS. The experimental results were measured bycounting the number of osteoclasts with 3 or more nuclei showingTRAP-positive reaction under a microscopic examination. Each of testswas confirmed over three times for gaining more reliable data.

As shown in the following table 7, the inhibitory effect of eachexperimental group on the differentiation of osteoclast versus controlswas expressed by inhibitory percentage value.

TABLE 7 % inhibitory activity on sample osteoclastogenesis 1 μm Example1 87.0 Example 2 78.4 Example 3 41.4 Example 4 81.1 Example 5 87.5Example 6 — Example 7 94.5 Example 8 88.3 Example 9 100 Example 10 1.8Example 11 53.2 Example 12 — Example 13 73.5 Example 14 89.2 Example 1568.3 Example 16 64.3 Example 17 59.1 Example 18 24.8 Example 19 42.6Example 20 35.6 Example 21 — Example 22 92.6 Example 23 47.7 Example 2457.8 Example 25 26.5 Example 26 42.9 Example 27 56.5 Example 28 29.6Example 29 96.3 Example 30 47.7 Example 31 35.6 Example 32 59.4 Example33 49.5 Example 34 28.7 Example 35 69.8 Example 36 46.4 Example 37 52.9Example 38 56.8 Example 39 37.5 Example 40 60.1 Example 41 64.0 Example42 90.9 Example 43 98.6 Example 44 96.6 Example 45 97.7 Example 46 96.9Example 47 90.0 Example 48 72.1 Example 49 77.1 Example 50 79.8 Example51 74.8 Example 52 0 Example 53 0 Example 54 94.2 Example 55 67.8Example 56 58.7 Example 57 60.4 Example 58 — Example 59 — Example 6028.2 Example 61 0 Example 62 19.1 1 m Example 63 56.5 Example 64 43.7Example 65 46.0 Example 66 38.5 Example 67 81.4 Example 68 83.0 Example69 99.6 Example 70 32.7 Example 71 — Example 72 67.9 Example 73 54.2Example 74 92.6 Example 75 40.2 Example 76 99.0 Example 77 83.3 Example78 97.5 Example 79 96.4 Example 80 96.4 Example 81 29.5 Example 82 8.9Example 83 23.8 Example 84 100 Example 85 5.3 Example 86 52.9 Example 8758.1 Example 88 15.9 Example 89 81.2 Example 90 61.9 Example 91 92.9Example 92 49.0 Example 93 63.7 Example 94 77.2 Example 95 47.1 Example96 64.3 Example 97 42.6 Example 98 94.7 Example 99 — Example 100 63.0Example 101 43.7 Example 102 96.4 Example 103 25.4 Example 104 40.0Example 105 61.1 Example 106 0 Example 107 53.2 Example 108 25.4 Example109 80.5 Example 110 100 Example 111 99.5 Example 112 76.8 Example 11386.7 Example 114 50.9 Example 115 96.0 Example 116 51.3 Example 117 2.7Example 118 82.9 Example 119 92.6 Example 120 35.7 Example 121 69.4Example 122 55.8 Example 123 26.3 Example 124 87.9 Example 125 73.0Example 126 71.2 Example 127 41.5 Example 128 75.5 Example 129 64.7Example 130 55.8 Example 131 69.0 Example 132 — Example 133 76.6 Example134 63.7 Example 135 48.6 Example 136 49.2 Example 137 62.7 Example 13891.0 Example 139 84.1 Example 140 18.9 Example 141 74.8 Example 142 54.1Example 143 69.5 Example 144 94.4 Example 145 96.2 Example 146 94.4Example 147 81.1 Example 148 90.1 Example 149 79.2 Example 150 95.4Example 151 93.0 Example 152 83.8 Example 153 96.4 Example 154 9.3Example 155 — Example 156 15.6 Example 157 92.3 Example 158 — Example159 — Example 160 83.7 Example 161 89.1 Example 162 87.4 Example 16388.1 Example 164 67.4 Example 165 66.9 Example 166 81.2 Example 167 99.0Example 168 87.0 Example 169 83.3 Example 170 93.9 Example 171 96.2Example 172 87.8 Example 173 9.0 Example 174 — Example 175 61.9 Example176 — Example 177 96.1 Example 178 36.8 Example 179 100 Example 180 32.6Example 181 54.1 Example 182 81.1 Example 183 65.6 Example 184 74.5Example 185 89.4 Example 186 71.0 Example 187 92.5 Example 188 82.6Example 189 38.7 Example 190 27.3 Example 191 8.8 Example 192 70.5Example 193 54.1 Example 194 19.8 Example 195 42.3 Example 196 82.0Example 197 — Example 198 36.9 Example 199 82.9 Example 200 38.7 Example201 85.6 Example 202 85.6 Example 203 68.8 Example 204 45.-7 Example 205— Example 206 — Example 207 14.4 Example 208 — Example 209 14.3 Example210 68.8 Example 211 44.0 Example 212 — Example 213 91.8

As shown in the table 7, the results indicate that the benzamidinederivatives were significantly inhibited the osteoclast differentiationat a low concentration.

Experimental Example 2 Effect on Bone Formation

The osteoblast, treated in this experiment, was prepared from theosteoblast as prepared in the above.

2-1: Experiment 1

The osteoblast, isolated from sequential enzymatic treatment ofcalvariae from neonated ICR mice, was cultured in α-MEM mediumcontaining 10% FBS for 4˜5 days. The osteoblast was also cultured for 24hr after seeding the cells on a 12 well plate (10⁵ cell/well), andmedium was exchanged with the osteogenic differentiation mediumcontaining 10 mM β-glycerophosphate and 50 μg/ml ascorbic acid.

The test substances at the concentration of 0.1 uM and 0.1 nM were addedto the above medium for evaluating the effect promoting bone formation.The differentiation medium containing the test substances was exchangedevery 3 or 4 days for 14 to 21 days until confirming the nodulemineralization.

The cell was rinsed twice with distilled water, and fixed by the 10%formalin solutions for 30 minutes. Alizarin red S and Von-kossa Solutionwere treated on the plate for measuring deposited calcium and phosphatein cell matrix, and the activity of the test substances on the boneformation was analyzed by determining stained area.

Additionally, for the purpose of estimating quantitative Arizarin red Sin cell matrix, stained Arizarin red S was extracted by treating 10 mMsodium phosphate solution (pH 7.0), containing 10% cetylpyridiniumchloride, for 15-30 minutes in the shaking incubator, and then theamount of the deposited calcium was estimated by calculating theabsorbance of the extracted Arizarin red S at 564 nm.

2-2: Experiment 2

1×10⁵ of calvarial cells per well from neonated ICR mice were loaded ona 12 well plate and cultured for 24 h. The osteogenic differentiationmedium containing 10 mM β-glycerophosphate and 50 μg/ml ascorbic acidwas exchanged at the confluent state of the cell, and the compounds forinvestigating their activities on the osteoblast were added.

The differentiation medium containing the test substances was exchangedevery 3 days, and the culturing period was prolonged approximately 15days.

The medium containing the test compounds was removed from the cells atthe end of culture and then, the cells were washed with sterilizeddistilled water once or twice and fixed to 10% formalin solution about30-60 minutes. These fixed plates were again washed once or twice, andstained 40 mM Arizarin red S for 10 minutes after drying the plates.These stained plates were rinsed 3˜5 times for eliminating wasteArizarin red S. For measuring the amount of the deposited Arizarin redS, 570 ul of 10% (w/v) cetylpyridinium chloride were added on plates,extracted and stained Arizarin red S for 15-30 minutes in the shakingincubator at 37° C. Finally, the amount of calcium was estimated bycalculating the absorbance of the extracted Arizarin red S at 564 nm.

The results are listed in in Table 8.

TABLE 8 bone forming activity (%) sample 0.1 μM 0.1 nM Example 7 9.611.24 Example 9 13.68 6.14 Example 14 12.06 10.56 Example 22 8.56 10.33Example 47 11.31 9.4 Example 110 9.37 9.76 Example 119 10.23 9.62Example 124 12.9 6.44 Example 129 11.54 11.18 Example 138 6.32 8.81

As shown in Table 8, benzamidine derivatives of the present inventionhave the excellent activities on the osteoblast, and thus thesecompounds are effective on the bone formation process.

Experimental Example 3 Therapeutic Effect in the OvariectomizedOsteoporetic Mouse Model of Each Test Substance

The therapeutic effects of each benzamidine derivates were evaluated onthe ovariectomized ddY mouse. Benzamidine derivates were dosed from 4weeks after operation for 4 weeks and the changes on the trabecular bonevolume (TBV) of the femur were observed via histomorphometry.

3-1. Animals and Husbandry

Female ddY mice (6-wk old upon receipt, SLC, Japan) were used afteracclimatization for 7 days. Animals were allocated 5 per polycarbonatecage in a temperature (20-25° C.) and humidity (30-35%) controlled room.Light:dark cycle was 12 hr:12 hr and feed (Samyang, Korea) and waterwere supplied free to access.

3-2. Preparations and Administration of Drugs

Salts of benzamidine derivates (Methansulfonic acid or HCl) were usedfor the test substances of this invention. Test substances are dissolvedand/or suspended in injectable distilled water and administered at adosage volume of 10 ml/kg by oral gavage. All test substances are dosedfrom 4 weeks after operation for 4 weeks at 50 mg/kg/day.

3-3. Ovariectomy

To induce estrogen-deficient osteoporosis, bilateral ovaries are removedand then closed by routine methods. Operation was conduct under Ketaminehydrochloride and xylazine hydrochloride anesthesia.

3-4. Histology

The left femur of each mouse were separated at sacrifice, and fixed in10% neutral buffered formalin (NBF), then decalcified in decalcifyingsolution (24.4% formic acid, and 0.5N sodium hydroxide) for 5 days(mixed decalcifying solution was exchanges once a day for 5 days). Afterthe dexalcification, the femur was embedded in paraffin, sectioned (3˜4μm) and stained with hematoxylin-eosin stain.

3-5. Histomorphometry

TBV was calculated using automated image analysis (analySIS ImageProcessing; SIS, Germany) under magnification of ×200 in the uniformarea of trochlea epiphyseal regions (growth plate regions were excluded)of prepared histological specimens. TBV was calculated as percentage (%)levels.

3-6. Changes vs Vehicle Control

The changes of TBV compared to that of vehicle control are calculated asfollowing Equation 1 to help the understanding of the efficacy of testsubstances.

Percentage changes=[((TBV of a−TBV of b)/TBV of b)×100]  Equation 1

a: test substance-dosing groups

b: vehicle control

Results are listed in Table 9.

TABLE 9 Changes on TBV (% changes vs vehicle sample control) Example 1381.97 Example 21 75.49 Example 23 28.03 Example 43 154.8 Example 47139.8 Example 111 69.26 Example 119 144.2 Example 124 72.82 Example 138164.17 Example 145 91.68 Example 165 37.52 Example 167 55.2 Example 16856.6 Example 169 186 Example 177 88.66 Example 184 146.66 Example 185152.06 Example 187 117.19 Example 188 91.96 Example 152 71.48

As shown in the table 9, the experimental results indicate that the testsubstances have inhibitory effects on the decrease of bone volumesinduced by ovariectomy. TBV of test substance-dosing groups aredramatically increased compared to that of vehicle control.

Therefore, it is considered that the test substances prove to beeffective for the treatment of osteoporosis.

Experimental Example 4 Effect of Promoting Fracture Healing in RibFracture-Induced at Model

The benzamidine compounds were assayed for therapeutic effect on bonefracture in rat models subjected to rib fracture. Benzamidine derivatesare dosed from 2 days after operation for 2 weeks, and the changes onthe volume and histology of callus were observed.

4-1. Experimental Animals and Breeding Management

A total of 54 SD rats (8 weeks old upon receipt, Jung Ang Lab. AnimalCo., Korea) were used. While being housed at a density of three to aplastic cage, the experimental animals were kept in a breeding roomunder controlled temperature (20-25° C.) and humidity (30-35%). Underlight-dark cycles of 12 hours, the rats were allowed to have free accessto feedstuff and tap water.

4-2. Preparations and Administration of Sample

200 mg of benzamidine compounds (Methansulfonic acid or Hydrochloride)were completely dissolved in 5 ml of sterilized distilled water. Thebenzamidine derivatives in the solutions was orally administered atdoses of 200 mg per kg of body weight once a day for 2 weeks from day 2of the surgery.

4-3. Induction of Rib-Fracture

8th and 9th rib of each animal was exposed by general operation underketamine HCl and xylazine HCl anesthesia, and the exposed ribs werecrossly dissected using surgical scissors. After rib-fracture, surgicalwounds were closed with general skin suture.

4-4. Volume of Bony Callus

8th and 9th ribs of each animal were separated at sacrifice and then thelong axis and short axis of callus were calculated as mm units. Thevolume of callus was calculated as following Equation 2.

Callus volume(mm³)=(a×b ²)/2  Equation 2

-   -   a: long diameter of bony callus    -   b: short diameter of bony callus

Results are listed in Table 10.

TABLE 10 Sample Changes on callus volume (mm³) Vehicle control 37.22 ±8.23  Example 13 23.15 ± 7.85* Example 47  27.56 ± 6.94** Example 11524.06 ± 9.64* Example 119  25.92 ± 10.35** Example 138 27.34 ± 5.46* *p< 0.01 compared to that of vehicle control **p < 0.05 compared to thatof vehicle control

As shown in the table 10, the experimental results indicate that thecallus volume of test substance-dosing groups are significantly (p<0.01or p<0.05) decreased compared to that of vehicle control.

Therefore, it is considered that the test substances have facilitatingeffects on the disappearance of callus volume induced by rib-fracture.

4-5. Histopathological Observation

The 8th rib including fracture sites of each rat was separated and fixedin 10% neutral buffered formalin, and then decalcified in decalcifyingsolution (24.4% formic acid, and 0.5N sodium hydroxide) for 5 days(mixed decalcifying solution was exchanges once a day for 5 days). Afterdecalcification, the rib was embedded in paraffin, sectioned (3˜4 μm)and stained with hematoxylin-eosin or Masson's trichrome for compositionof callus observation.

Osteloid volume (OV/callus) in callus regions of prepared histologicalspecimens were detected as % levels using automated image analysis(analySIS Image Processing; SIS, Germany) under microscopy.

Results are listed in Table 11.

TABLE 11 Changes on callus osteoid volume sample (OV/callus, %) Vehiclecontrol 35.88 ± 5.06 Example 13  43.19 ± 4.47** Example 47 45.69 ± 7.07Example 115 41.94 ± 6.33 Example 119  50.18 ± 8.42* Example 138  53.83 ±7.84* *p < 0.01 compared to that of vehicle control **p < 0.05 comparedto that of vehicle control

As shown in the table 11, the experimental results indicate that thecallus osteoid volume of test substance-dosing groups are significantly(p<0.01 or p<0.05) increased compared to that of vehicle control.

Therefore, it is considered that the test substances have favorableeffects on the facilitating the ossification in the callus induced byrib-fracture.

Experimental Example 5 Therapeutic Effect in Mouse Model of AsthmaInduced with Ovalbumin

The benzamidine compounds were assated for therapeutic effect onallergic inflammation in mouse models of ovalbumin-induced asthma.Starting on the day of immunization the benzamidine compounds were dosedfor 17 consecutive days. The experimental animals were re-exposed toovalbumin 14 days after the sensitization and then sacrificed 3 daysafter the re-exposure. Changes in lung weight, cellular components ofperipheral blood and bronchoalveolar lavage fluid, and lunghistopathology were observed.

5-1. Experimental Animals and Breeding Management

A total of 110 female C57BL/6 mice (7-week-old, SLC, Japan) were adaptedto a laboratory environment for 6 days before being used in earnestexperiments. While being housed at a densirt of five in a plastic cage,the experimental animals were breed in a breeding room with controlledtemperature (20-25° C.) and humidity (30-35%). Under light-dark cyclesof 12 hours, mice were allowed to have free access to feedstuff and tapwater. While asthma was induced in 100 mice by ovalbumin, 10 mice wereused as a non-treated group.

5-2. Preparations and Administration of Sample

200 mg of benzamidine compounds (Methansulfonic acid or Hydrochloride)were completely dissolved in 5 ml of sterilized distilled water. Thebenzamidine compound in the solutions was orally administered at dosesof 200 mg per kg of body weight once a day from the day of thesensitization with ovalbumin. The control group was administered withequal volumes of sterilized distilled water in the same manner.

5-3. Asthma Induction by Immunization with and Exposure to Ovalbumine

A solution of 200 μg of ovalbumin (Grade VI; Sigma, st. Louis, Mo., USA)and 180 mg of aluminium hydroxide (Al(OH)₃, dried powder gel; Aldrich,Milwaukee, USA) in 4 ml of physiological saline was allowed to stand at4° C. overnight and was administered to the experimental animals (200μl, abdominal injection) for sensitization. As for the non-treatedgroup, a solution of only aluminium hydroxide in saline was injected. 15days after sensitization, a 1.5% ovalbumin solution was sprayed in airusing a nebulizer, followed by exposing the experimental animals to thespray for 10 min to induce asthma therein. The non-treated group wasexposed only to saline in the same manner. All the experimental animalswere sacrificed 3 days after the exposure.

5-4. Measurement of Lung Weight

On the final day of experiment, the lungs were separated form adjacentorgans. The removed lungs were weight among individual animals, therelative weight of the lungs was calculated as a percentage of bodyweight using the following Equation 3.

Relative weight of Lung(%)=(Absolute lung weight/Bodyweight)×100  Equation 3

Results are listed in Table 12.

TABLE 12 Changes on the lung weight Group Absolute (g) Relative (%) Sham(?) 0.110 ± 0.009  0.694 ± 0.049 Vehicle control 0.134 ± 0.012*  0.780 ±0.103** Example 13 0.108 ± 0.009# 0.695 ± 0.075 Example 47     0.122 ±0.010**, ## 0.706 ± 0.059 Example 115 0.114 ± 0.009# 0.705 ± 0.046Example 119 0.113 ± 0.010# 0.720 ± 0.103 Example 138 0.113 ± 0.011# 0.691 ± 0.065## Example 169 0.113 ± 0.003#  0.696 ± 0.032## Example 1850.116 ± 0.003# 0.720 ± 0.061 *p < 0.01 compared to that of sham **p <0.05 compared to that of sham #p < 0.01 compared to that of vehiclecontrol ##p < 0.05 compared to that of vehicle control

As shown in the table 12, significantly (p<0.01 or p<0.05) increase ofabsolute and relative lung weights are detected in vehicle controlcompared to those of sham. However, they were significantly (p<0.01 orp<0.05) or dramatically decreased in test substance-dosing groupscompared to that of vehicle control.

Therefore, it is considered that the test substances inhibit theincrease of lung weight induced by asthmatic changes.

5-5. Changes on the Total Count of Leukocytes in the Peripheral Bloodand BALF a) Total Count of Leukocytes in Peripheral Blood

On the final day of experiment, all the experimental animals wereetherized and underwent laparotomy to expose the abdominal vena cava,from which 1 ml of blood was the taken. Using a hemocytometer, a bloodsample was measured for total leukocyte counts in a ×10³/1 mm³ units.

b) Total Count of Leukocytes in BALF

On the final day of experiment, secretions present in bronchi andalveola were examined for cyrological constitution. After veingetherized, the experimental animals were operated to open the cervicalregion and the thorax. The jugular vein was allowed to bleed, followedby endotracheal intubation. 3 ml of phosphate buffered saline wasinjected twice through the tube and the thorax was massaged for 30 secto obtain cell suspension from the lungs. Using a hemocytometer, a bloodsample was measured for total leukocyte counts in a ×10⁵/1 ml units.

Results are listed in Table 13.

TABLE 13 Total leukocytes in peripheral blood Total leukocytes in Group(×10³/1 mm³) BALF (×10⁵/1 ml) Sham 10.27 ± 0.93  51.75 ± 2.15  Vehiclecontrol 14.49 ± 0.88* 75.68 ± 4.67* Example 13 14.06 ± 1.07* 72.75 ±4.88  Example 47    12.55 ± 1.35*, #    62.40 ± 7.56*, # Example 11913.83 ± 1.27* 74.75 ± 6.33* Example 138    13.60 ± 0.83*, #    68.83 ±5.29*, ## Example 169 13.20 ± 2.22* 72.25 ± 7.95* Example 185    11.90 ±1.45**, #    66.47 ± 7.41*, # *p < 0.01 compared to that of sham **p <0.05 compared to that of sham #: p < 0.01 compared to that of vehiclecontrol ##: p < 0.05 compared to that of vehicle control

As shown in the table 13, significant (p<0.01) increase of totalleukocytes in peripheral blood and BALF are detected in vehicle controlcompared to those of sham, respectively. However, they weresignificantly (p<0.01 or p<0.05) or dramatically decreased in the testsubstance-dosing groups compared to that of vehicle control,respectively.

Therefore, it is considered that the test substances have favorableeffects on the inhibition of the inflammatory responses induced byasthmatic changes.

Experimental Example 6 Cytotoxicity Test

Cytotoxic effect of benzamidine derivatives was evaluated by theexperiment described below.

The test substance was diluted in appropriate solvent at 10⁻²Mconcentration. This substance was diluted in culture medium at 10⁻⁵concentration, and loaded into a 96-well microplate in a dose of 100 μLper well. Cells to be used in cytotoxitic test were plated on a 96-wellmicroplate in a dose of 1×10⁴ cell/100 μL per well and cultured for 72hrs. 25 μL of MTT[3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide]dissolved in PBS at 2 mg/mL were added before 4 hrs of the end ofculture. After reaction, the plates were centrifuged, medium wasdecanted and 100 μL of DMSO was added to dissolve formazan. Lastly, theabsorbance of developed plates was measured at 540 nm. Survival rates ofthe cells were showed by % concentration compared with the controlgroup.

Results were displayed in table 14.

TABLE 14 Survival rates of the cells (10⁻⁶ M) sample MC3T3-E1 ST2Example 47 54.2 24.0 Example 8 76.9 46.2 Example 11 87.2 33.1 Example 1581.8 42.3 Example 16 39.6 30.1 Example 32 100.0 55.1 Example 35 73.656.3 Example 37 74.4 40.5 Example 40 100.0 53.3 Example 41 84.6 48.7Example 45 75.9 37.0 Example 46 100.0 48.3 Example 48 100.0 51.2 Example49 83.5 39.0 Example 50 81.0 61.0 Example 51 95.5 66.5 Example 57 52.119.9 Example 63 52.5 29.3 Example 67 68.9 40.0 Example 86 100.0 48.6Example 87 97.3 49.8 Example 88 94.3 48.7 Example 91 41.3 20.8 Example93 66.8 55.0 Example 96 65.1 27.8 Example 98 77.1 26.9 Example 100 62.839.1 Example 107 65.2 43.9 Example 109 65.7 39.0 Example 112 86.7 63.6Example 118 75.3 53.2 Example 121 100.0 41.4 Example 125 57.6 47.9Example 126 42.7 31.8 Example 130 100.0 37.2 Example 133 62.6 46.4Example 134 43.9 37.4 Example 136 48.5 29.9 Example 139 77.4 48.1Example 141 52.8 27.9 Example 146 88.4 38.2 Example 147 100.0 42.4Example 166 71.2 52.4 Example 181 99.5 36.7

As shown in table 14, benzamidine derivative shows little cytotoxicity.

Examples of preparation of this invention are following.

Formulation Example 1. Preparation of Powders

Benzamidine derivatives 2 g lactose 1 g

2 g of benzamidine derivatives of the formula (1) was mixed with 1 g oflactose, thus preparing powder from the mixture with filling to a airtight bag.

2. Preparation of Tablets

Benzamidine derivatives 100 mg corn starch 100 mg lactose 100 mgmagnesium stearate  2 mg

After mixing all components, tablets are prepared by being tableted withgenerally used methods.

3. Preparation of Capsules

Benzamidine derivatives 100 mg corn starch 100 mg lactose 100 mgmagnesium stearate  2 mg

After mixing all components, capsules are prepared by being filled up togelatin capsules with generally used methods.

4. Preparation of Injections

Benzamidine derivatives 10 μg/ml dilute hydrochloric acid BP to pH 3.5NaCl for injections BP Max. 1 ml

Benzamidine derivatives of the formula 1 was dissolved in adequatevolume of NaCl for injections BP, then pH of the solution was controlledto pH 3.5 with dilute hydrochloric acid BP. The volume of the wholesolution was fixed with NaCl for injections BP, and the solution wasmixed fully. The solution was filled up to type I ampoule made withglass, then the ampoule was sealed under the upper air lattice bymelting glass. The sealed ampoule was autoclaved under the condition of120° C. for 15 mins or more to prepare the sterilized injection.

INDUSTRIAL APPLICABILITY

The novel benzamidine derivatives of the present invention remarkablysuppress osteoclastic bone resorption, stimulate osteoblastic boneformation in very low concentrations and inhibit decreases of bone massin osteoporosis animal models and thus are useful for the prevention andtreatment of osteoporosis. Further, the compounds of the presentinvention activate the loss of bony callus and its ossification and thusare useful for the prevention and treatment of bone fractures. Thecompounds of the present invention are also useful for the preventionand treatment of allergic inflammatory diseases.

1. Benzamidine derivate of the formula 1 or pharmaceutically acceptablesalts thereof.

wherein R₁ is C₁˜C₆ alkyl; C₃˜C₆ cycloalkyl; phenyl; benzyl; pyridinyl;guanidino; NR₆R₇; CH₂NR₆R₇;

 wherein A is C₁˜C₆ alkyl and n is an integer of 2 to 6; C₁˜C₆ alkylwhich is substituted by pyridine or

 wherein

 is unsubstituted or substituted by hydroxy; pyridinyl or

 which is substituted by C₁˜C₆alkyl; R₂ is hydrogen; C₁˜C₆ alkyl; C₃˜C₆cycloalkyl; phenyl; benzyl; C₁˜C₆ alkyl which is substituted by hydroxy,C₁˜C₆ alkoxy, halogen or C₃˜C₆ cycloalkyl; C₂˜C₆ alkenyl; R₃ and R₄,each independently, are hydrogen; halogen; hydroxy; C₁˜C₆ alkyl which isunsubstituted or substituted halogen; C₃˜C₆ cycloalkylamino; C₁˜C₆alkoxy; C₁˜C₆ alkanoyloxy; C₂˜C₆ alkenyloxy; phenyl-C₁˜C₆ alkoxy;phenoxy; C₂˜C₆ alkenoyloxy or phenyl-C₁˜C₆ alkanoyloxy; C₃˜C₆cycloalkyloxy which is substituted by carboxy, esterified carboxy oramidated carboxy; aminooxy; R₅ is hydrogen or hydroxy; R₆ and R₇, eachindependently, are hydrogen; C₁˜C₆ alkyl; phenyl; benzyl; pyridinyl;C₁˜C₆alkyl which is substituted by pyridine or

 carbonyl which is substituted by C₁˜C₆ alkyl, phenyl, benzyl, pyridineor

 C₁˜C₆ alkanesulfonyl; C₁˜C₆ alkyl which is substituted by hydroxy orC₁˜C₆ alkoxy; acetyl which is substituted by hydroxy or C₁˜C₆ alkoxy; Yis oxygen; sulfur; NR₆, or CH₂; X₁ and X₃, each independently, areoxygen; sulfur; NH; N—C₁˜C₆alkyl; N—C₃˜C₆cycloalkyl; N-benzyl; N-phenyl;X₂ is C₃-C₇ alkylene; C₁-C₃ alkylene-alkenylene-C₁-C₃-alkylene; C₁-C₃alkylene-O—C₁-C₃ alkylene; C₁-C₃ alkylene-S—C₁-C₃ alkylene; C₁-C₃alkylene-NH—C₁-C₃ alkylene; C₁-C₃ alkylene-phenylene-C₁-C₃ alkylene;C₁-C₃ alkylene-pyridylene-C₁-C₃ alkylene; C₁-C₃alkylene-naphtylene-C₁-C₃ alkylene; C₃-C₇ alkylene which is substitutedby C₁-C₃ alkyl and hydroxy; C₃-C₇ alkylenecarbonyl; C₃-C₇ alkylene whichis interrupted by piperazine; with the proviso that if X₁ and X₃ areoxygen, X₂ is pentyl and R₃ and R₄ are hydrogen, the compound of theformula 1 wherein R₁ is methyl and R₂ is isopropyl is excluded.
 2. Thecompound according to claim 1, wherein R₁ is C₁˜C₅ alkyl; C₃˜C₆cycloalkyl; phenyl; pyridinyl; guanidino; NR₆R₇; CH₂NR₆R₇;

 wherein A is C₁˜C₆ alkyl and n is an integer of 2 to 6; C₁˜C₆ alkylwhich is substituted by

 wherein

 is unsubstituted or substituted by hydroxy;

 which is substituted C₁˜C₆ alkyl; R₂ is hydrogen; C₁˜C_(s) alkyl; C₃˜C₆cycloalkyl; benzyl; C₁˜C₆ alkyl which is substituted by hydroxyl,methoxy, halogen or C₃˜C₆ cycloalkyl; C₂˜C₆ alkenyl; R₃ and R₄, eachindependently, are hydrogen; halogen; hydroxy; C₃˜C₆ cycloalkylamino;C₁˜C₆ alkoxy; C₁˜C₆ alkanoyloxy; C₃˜C₆ cycloalkyloxy which issubstituted by carboxy, esterified carboxy or amidated carboxy;aminooxy; R₅ is hydrogen or hydroxy; R₆ and R₇, each independently, arehydrogen; C₁˜C₆ alkyl; benzyl; pyridinyl; C₁˜C₆ alkyl which issubstituted by pyridine or

 carbonyl which is substituted by pyridine or C₁˜C₆ alkyl; C₁˜C₆alkanesulfonyl; C₁˜C₆ alkyl which is substituted by hydroxy or C₁˜C₆alkoxy; acetyl which is substituted by hydroxy or C₁˜C₆ alkoxy; Y isoxygen; sulfur; NR₆; CH₂; X₁ and X₃, each independently, are oxygen;sulfur; NH; N—C₁˜C₆ alkyl; X₂ is C₃-C₇ alkylene; C₁-C₃alkylene-alkenylene-C₁-C₃-alkylene; C₁-C₃ alkylene-O—C₁-C₃ alkylene;C₁-C₃ alkylene-NH—C₁-C₃ alkylene; C₁-C₃ alkylene-phenylene-C₁-C₃alkylene; C₁-C₃ alkylene-pyridylene-C₁-C₃ alkylene; C₁-C₃alkylene-naphtylene-C₁-C₃ alkylene; C₃-C₇ alkylene which is substitutedby C₁-C₃ alkyl or hydroxy; C₃-C₇ alkylenecarbonyl; C₃-C₇ alkylene whichis interrupted by piperazine; or pharmaceutically acceptable saltsthereof.
 3. The compound according to claim 2, wherein R₁ is methyl;ethyl; propyl; isopropyl; butyl; t-butyl; pentyl; cyclopentyl; hexyl;cyclohexyl; phenyl; aminomethyl; aminoethyl; amino; isobutylamide;guanidine; 1-propyl-piperidino; 2-morpholinomethyl; NR₆R₇; CH₂NR₆R₇;

 wherein A is C₁˜C₆ alkyl and n is an integer of 2 to 6; pyridinyl;4-hydroxypiperidinomethyl; cyclohexylaminomethyl; R₂ is hydrogen;methyl; ethyl; isopropyl; propyl; butyl; isobutyl; methoxymethyl;hydroxymethyl; 2-methylpropyl; pentyl; chloromethyl; chloroethyl;cyclopentyl; cyclopentylmethyl; cyclohexyl; benzyl; vinyl; R₃ and R₄,each independently, are hydrogen; halogen; hydroxy; cyclohexylamino;methoxy; C₁-C₄ alkanoyloxy; C₁-C₇ aliphatic alkoxy which is substitutedby carboxy, esterified carboxy or amidated carboxy; R₅ is hydrogen orhydroxy; R₆ and R₇, each independently, are hydrogen; methyl; ethyl;propyl; benzyl; pyridin-3-yl; pyridin-4-yl; 2-morpholinoethyl;4-pyridinylcarbonyl; 3-pyridinylcarbonyl; isobutylcarbonyl;ethanesulfonyl; methoxyethyl; hydroxyethyl; hydroxyacetyl;methoxyacetyl; Y is oxygen; sulfur; NR₆; CH₂; X₁ and X₃, eachindependently, are oxygen; sulfur; amine; methylamine; X₂ is propylene;butylene; pentylene; hexylene; heptylene; ethylene-O-ethylene;3-hydroxy-3-methyl-pentylene; methylethylene-NH-ethylene;ethylene-NH-ethylene; propylene which is interrupted by piperazine;butylene carbonyl; 2-butenyl; methylene-phenylene-methylene;methylene-pyridylene-methylene; 1,2-ethylene-1,4-phenylene-1,2-ethylene;1,3-propylene-1,4-phenylene-1,3-propylene;1,2-ethylene-naphthalene-1,2-ethylene; or pharmaceutically acceptablesalts thereof.
 4. The compound according to claim 3, wherein R₁ ismethyl; ethyl; isopropyl; cyclohexyl; phenyl; aminomethyl; aminoethyl;amino; pyridinyl; NR₆R₇; CH₂NR₆R₇;

 wherein A is C₁˜C₂ alkyl and n is an integer of 4 to 5; R₂ is hydrogen;methyl; ethyl; isopropyl; isobutyl; methoxymethyl; hydroxymethyl;chloromethyl; chloroethyl; cyclopentyl; cyclopentylmethyl; vinyl; R₃ andR₄, each independently, are hydrogen; halogen; hydroxy; methoxy; R₅ ishydrogen or hydroxy; R₆ and R₇, each independently, are hydrogen;methyl; ethyl; benzyl; pyridin-3-yl; pyridin-4-yl; 2-morpholinoethyl;4-pyridinylcarbonyl; 3-pyridinylcarbonyl; isobutylcarbonyl;ethanesulfonyl; hydroxyethyl; methoxyethyl; Y is oxygen; sulfur;methylamine; X₁ and X₃, each independently, are oxygen; sulfur; amino;methylamine; X₂ is propylene; butylene; pentylene; hexylene;ethylene-O-ethylene; ethylene-NH-ethylene; butylenecarbonyl; 2-butenyl;methylene-1,2-phenylene-methylene; methylene-1,3-phenylene-methylene;methylene-1,4-phenylene-methylene; methylene-pyridinyl-methylene;pharmaceutically acceptable salts thereof.
 5. The compound according toclaim 1, wherein pharmaceutically acceptable salt is hydrogen chloridesalt or methanesulfonic acid salt.
 6. The compound according to claim 1which is selected from the group consisting of 1)N-hydroxy-4-5-[4-(2-isopropyl-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,2)4-5-[4-(2-isopropyl-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,3)N-hydroxy-4-5-[4-(2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,4)N-hydroxy-4-5-[4-(2-ethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,5)N-hydroxy-4-5-[4-(2-isopropyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,6)N-hydroxy-4-5-[4-(2-phenyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,7)N-hydroxy-4-5-[4-(2-pyridin-3-yl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,8)N-hydroxy-4-5-[4-(2-cyclohexyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,9)N-hydroxy-4-5-[4-(2-pentyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,10)N-hydroxy-4-5-[4-(2,5-dimethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,11)N-hydroxy-4-5-[4-(2-ethyl-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,12)N-hydroxy-4-5-[4-(5-methyl-2-phenyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,13)N-hydroxy-4-5-[4-(5-methyl-2-pyridin-3-yl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,14)N-hydroxy-4-5-[4-(2-cyclohexyl-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,15)N-hydroxy-4-5-[4-(5-methyl-2-pentyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,16)N-hydroxy-4-5-[4-(2-t-butyl-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,17)N-hydroxy-4-5-[4-(5-ethyl-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,18)N-hydroxy-4-5-[4-(2,5-diethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,19)N-hydroxy-4-5-[4-(5-ethyl-2-isopropyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,20)N-hydroxy-4-5-[4-(5-ethyl-2-phenyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,21)N-hydroxy-4-5-[4-(5-ethyl-2-pyridin-3-yl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,22)N-hydroxy-4-5-[4-(2-cyclohexyl-5-ethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,23)N-hydroxy-4-5-[4-(5-ethyl-2-pentyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,24)N-hydroxy-4-5-[4-(2-ethyl-5-isopropyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,25)N-hydroxy-4-5-[4-(2,5-diisopropyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,26)N-hydroxy-4-5-[4-(5-isopropyl-2-phenyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,27)N-hydroxy-4-5-[4-(5-isopropyl-2-pyridin-3-yl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,28)N-hydroxy-4-5-[4-(5-isopropyl-2-pentyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,29)N-hydroxy-4-5-[4-(2-methyl-5-propyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,30)N-hydroxy-4-5-[4-(5-butyl-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,31)N-hydroxy-4-5-[4-(5-butyl-2-ethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,32)N-hydroxy-4-5-[4-(5-butyl-2-isopropyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,33)N-hydroxy-4-5-[4-(5-butyl-2-phenyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,34)N-hydroxy-4-5-[4-(5-butyl-2-pyridin-3-yl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,35)N-hydroxy-4-5-[4-(5-butyl-2-cyclohexyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,36)N-hydroxy-4-5-[4-(5-butyl-2-pentyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,37)N-hydroxy-4-5-[4-(5-butyl-2-t-butyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,38)N-hydroxy-4-5-[4-(5-benzyl-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,39)N-hydroxy-4-5-[4-(5-benzyl-2-isopropyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,40)N-hydroxy-4-5-[4-(5-benzyl-2-phenyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,41)N-hydroxy-4-5-[4-(5-benzyl-2-pyridin-3-yl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,42)N-hydroxy-4-5-[4-(5-(2-chloro-ethyl)-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,43)N-hydroxy-4-5-[4-(5-cyclopentyl-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,44)N-hydroxy-4-5-[4-(5-isobutyl-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,45)N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,46)N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-ethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,47)N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-isopropyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,48)N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-phenyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,49)N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-pyridin-3-yl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,50)N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-cyclohexyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,51)N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-pentyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,52) 4-5-[4-(2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine, 53)4-5-[4-(2-isopropyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine, 54)4-5-[4-(2,5-dimethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine, 55)4-5-[4-(5-ethyl-2-isopropyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,56)4-5-[4-(5-ethyl-2-phenyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,57)N-hydroxy-4-5-[4-(2-amino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,58)N-hydroxy-4-5-[4-(2-amino-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,59)N-hydroxy-4-5-[4-(2-guanidino-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,60)N-hydroxy-4-5-[4-(2-amino-5-ethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,61)N-hydroxy-4-5-[4-(2-amino-5-isopropyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,62)N-hydroxy-4-5-[4-(2-guanidino-5-isopropyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,63)N-hydroxy-4-5-[4-(2-amino-5-butyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,64)N-hydroxy-4-5-[4-(5-butyl-2-guanidino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,65)N-hydroxy-4-5-[4-(2-amino-5-benzyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,66)N-hydroxy-4-5-[4-(5-benzyl-2-guanidino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,67)N-hydroxy-4-5-[4-(2-amino-5-cyclopentylmethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,68)N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-(1-propyl-piperidin-4-yl)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,69)N-hydroxy-4-5-[4-(2-(isobutyryl)amino-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine70)N-hydroxy-4-5-[4-(5-isopropyl-2-morpholinomethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,71)N-hydroxy-4-5-[4-(2-aminomethyl-5-benzyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,72)N-hydroxy-4-5-[4-(5-methyl-2-(1-propyl-piperidin-4-yl)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,73)N-hydroxy-4-5-[4-(5-isopropyl-2-aminomethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,74)N-hydroxy-4-5-[4-(5-vinyl-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,75)N-hydroxy-4-5-[4-(5-hydroxymethyl-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,76)N-hydroxy-4-5-[4-(5-methoxymethyl-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,77)N-hydroxy-4-5-[4-(5-(2-chloroethyl)-2-amino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,78)N-hydroxy-4-5-[4-(5-vinyl-2-amino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,79)N-hydroxy-4-5-[4-(5-vinyl-2-(pyridin-3-yl)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,80)N-hydroxy-4-5-[4-(5-(2-chloroethyl)-2-(pyridin-3-yl)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,81)N-hydroxy-4-5-[4-(2-amino-5-cyclopentyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,82)N-hydroxy-4-5-[4-(5-ethyl-2-aminomethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,83)N-hydroxy-4-5-[4-(5-isopropyl-2-(piperidin-3-yl)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,84)N-hydroxy-4-5-[4-(2-ethylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,85)N-hydroxy-4-5-[4-(2-ethanesulfonylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,86)N-hydroxy-4-5-[4-(5-methyl-2-methylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,87)N-hydroxy-4-5-[4-(2-ethylamino-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,88)N-hydroxy-4-5-[4-(5-methyl-2-propylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,89)N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-(3-pyridylcarbonyl)amino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,90)N-hydroxy-4-5-[4-(2-hydroxyacetylamino-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,91)N-hydroxy-4-5-[4-(5-methyl-2-(4-pyridylcarbonyl)amino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,92)N-hydroxy-4-5-[4-(5-methyl-2-(3-pyridylcarbonyl)amino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,93)N-hydroxy-4-5-[4-(2-ethanesulfonylamino-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,94)N-hydroxy-4-5-[4-(2-(2-methoxyethyl)amino-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,95)N-hydroxy-4-5-[4-(2-ethanesulfonylamino-5-ethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,96)N-hydroxy-4-5-[4-(5-ethyl-2-methylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,97)N-hydroxy-4-5-[4-(5-ethyl-2-ethylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,98)N-hydroxy-4-5-[4-(5-ethyl-2-propylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,99)N-hydroxy-4-5-[4-(5-ethyl-2-methoxyacetylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,100)N-hydroxy-4-5-[4-(5-ethyl-2-(4-pyridylcarbonyl)amino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,101)N-hydroxy-4-5-[4-(5-ethyl-2-(3-pyridylcarbonyl)amino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,102)N-hydroxy-4-5-[4-(5-ethyl-2-(2-methoxyethyl)amino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,103)N-hydroxy-4-5-[4-(5-isopropyl-2-methylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,104)N-hydroxy-4-5-[4-(2-ethylamino-5-isopropyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,105)N-hydroxy-4-5-[4-(5-butyl-2-methylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,106)N-hydroxy-4-5-[4-(5-butyl-2-ethylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,107)N-hydroxy-4-5-[4-(5-benzyl-2-methylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,108)N-hydroxy-4-5-[4-(5-benzyl-2-ethylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,109)N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-methylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,110)N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-ethylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,111)N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-propylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,112)N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-(4-pyridylcarbonyl)amino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,113)N-hydroxy-4-5-[4-(5-cyclopentyl-2-propylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,114)N-hydroxy-4-5-[4-(5-isopropyl-2-[(pyridin-3-yl-methyl)amino]-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,115)N-hydroxy-4-5-[4-(5-(2-chloroethyl)-2-methylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,116)N-hydroxy-4-5-[4-(2-methylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,117)N-hydroxy-4-5-[4-(5-ethyl-2-[(pyridin-3-yl-methyl)amino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,118)N-hydroxy-4-5-[4-(2-(ethanesulfonyl-methyl-amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,119)N-hydroxy-4-5-[4-(2-methyl-(2-morpholinoethyl)amino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,120)N-hydroxy-4-5-[4-(2-(2-hydroxyethyl)-methyl-amino-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,121)N-hydroxy-4-5-[4-(2-(ethyl-(2-hydroxyethyl)-amino)-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,122)N-hydroxy-4-5-[4-(2-(bis-(2-methoxyethyl)-amino)-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,123)N-hydroxy-4-5-[4-(5-methyl-2-(methyl-(2-morpholinoethyl)-amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,124)N-hydroxy-4-5-[4-(2-(ethyl-1-(2-morpholinoethyl)-amino)-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,125)N-hydroxy-4-5-[4-(2-(benzyl-methyl-amino)-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,126)N-hydroxy-4-5-[4-(5-methyl-2-(methyl-pyridin-3-yl-methyl-amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,127)N-hydroxy-4-5-[4-(2-(benzyl-ethyl-amino)-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,128)N-hydroxy-4-5-[4-(2-(bis-(2-hydroxyethyl)-amino)-5-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,129)N-hydroxy-4-5-[4-(5-ethyl-2-((2-hydroxyethyl)-methyl-amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,130)N-hydroxy-4-5-[4-(5-ethyl-2-(ethyl-(2-hydroxyethyl)-amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,131)N-hydroxy-4-5-[4-(5-ethyl-2-(methyl-(2-morpholinoethyl)-amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,132)N-hydroxy-4-5-[4-(5-ethyl-2-(ethyl-(2-morpholinoethyl)-amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,133)N-hydroxy-4-5-[4-(2-(benzyl-methyl-amino)-5-ethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,134)N-hydroxy-4-5-[4-(5-ethyl-2-(methyl-(pyridin-3-yl-methyl)amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,135)N-hydroxy-4-5-[4-(2-(benzyl-ethyl-amino)-5-ethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,136)N-hydroxy-4-5-[4-(5-ethyl-2-(ethyl-(pyridin-3-yl-methyl)amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,137)N-hydroxy-4-5-[4-(2-(bis-(pyridin-3-yl-methyl)amino)-5-ethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,138)N-hydroxy-4-5-[4-(2-dipropylamino-5-ethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,139)N-hydroxy-4-5-[4-(2-(bis-(2-hydroxyethyl)amino)-5-ethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,140)N-hydroxy-4-5-[4-(2-((2-hydroxyethyl)-methyl-amino)-5-isopropyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,141)N-hydroxy-4-5-[4-(5-isopropyl-2-(methyl-(pyridin-3-yl-methyl)amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,142)N-hydroxy-4-5-[4-(2-(ethanesulfonyl-methyl-amino)-5-isopropyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,143)N-hydroxy-4-5-[4-(5-butyl-2-((2-hydroxyethyl)-methyl-amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,144)N-hydroxy-4-5-[4-(5-butyl-2-(methyl-(2-morpholinoethyl)amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,145)N-hydroxy-4-5-[4-(5-butyl-2-(methyl-(pyridin-3-yl-methyl)amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,146)N-hydroxy-4-5-[4-(5-butyl-2-dipropylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,147)N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-(methyl-(pyridin-3-yl-methyl)amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,148)N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-(methyl-(2-morpholinoethyl)amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,149)N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-dipropylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,150)N-hydroxy-4-5-[4-(5-butyl-2-diethylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,151)N-hydroxy-4-5-[4-(5-butyl-2-ethylmethylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,152)N-hydroxy-4-5-[4-(5-butyl-2-dimethylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,153)N-hydroxy-4-[5-(4-5-cyclopentyl-2-[methyl-(2-morpholinoethyl)amino]-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,154)N-hydroxy-4-[5-(4-5-isobutyl-2-[methyl-(2-morpholinoethyl)amino]-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,155)N-hydroxy-4-5-[4-(5-(2-chloroethyl)-2-dimethylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,156)N-hydroxy-4-5-[4-(5-cyclopentyl-2-diethylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,157)N-hydroxy-4-5-[4-(5-isopropyl-2-dipropylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,158)N-hydroxy-4-5-[4-(5-ethyl-2-diethylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,159)N-hydroxy-4-[5-(4-5-isopropyl-2-[methyl-(2-morpholinoethyl)amino]-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,160)N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-diethylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,161)N-hydroxy-4-5-[4-(5-isopropyl-2-dimethylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,162)N-hydroxy-4-5-[4-(5-isopropyl-2-diethylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,163)N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-dimethylamino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,164)N-hydroxy-4-5-[4-(5-methyl-2-piperidino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,165)N-hydroxy-4-5-[4-(5-methyl-2-morpholino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,166)N-hydroxy-4-5-[4-(5-ethyl-2-piperidino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,167)N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-piperidino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,168)N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-morpholino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,169)N-hydroxy-4-5-[4-(5-isopropyl-2-morpholino-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine170)N-hydroxy-4-5-4-[5-cyclopentylmethyl-2-(4-methylpiperazino)-1,3-thiazol-4-yl]phenoxy-pentoxy-benzamidine,171)N-hydroxy-4-5-[4-(5-vinyl-2-morpholin-4-yl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,172)N-hydroxy-4-5-[4-(5-cyclopentyl-2-morpholin-4-yl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,173)N-hydroxy-4-5-[4-(5-isobutyl-2-morpholin-4-yl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,174)N-hydroxy-4-5-4-[5-ethyl-2-(4-methylpiperazino)-1,3-thiazol-4-yl]phenoxy-pentoxy-benzamidine,175)N-hydroxy-4-5-[4-(2-morpholin-4-yl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,176)N-hydroxy-4-5-4-[5-isopropyl-2-(4-methylpiperazino)-1,3-thiazol-4-yl]phenoxy-pentoxy-benzamidine,177)N-hydroxy-4-5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)phenoxy]-pentylamino-benzamidine,178)N-hydroxy-4-2-[2-(4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)phenoxy)-ethoxy]-ethoxy-benzamidine,179)N-hydroxy-4-3-hydroxy-5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)-phenoxy]-3-methyl-pentoxy-benzamidine,180)N-hydroxy-4-2-[2-(4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)-phenoxy)-1-methyl-ethylamino]-ethoxy-benzamidine,181)N-hydroxy-4-3-[4-(3-(4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)-phenoxy)-propyl)-piperazin-1-yl]-propoxy-benzamidine,182)N-hydroxy-4-5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)-phenoxy]-pentanoyl-amino-benzamidine,183)N-hydroxy-4-5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)-phenoxy]-pentyl-methyl-amino-benzamidine,184)N-hydroxy-4-4-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)-phenoxy]-2-butenyloxy-benzamidine,185)N-hydroxy-4-4-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)-phenoxymethyl]-benzyloxy-benzamidine,186)N-hydroxy-4-2-[2-(4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)phenoxy)-ethylamino]-ethoxy-benzamidine,187)N-hydroxy-2-fluoro-4-5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)-phenoxy]-pentoxy-benzamidine,188)2,N-dihydroxy-4-5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)-phenoxy]-pentoxy-benzamidine,189)N-hydroxy-4-5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)-phenoxy]-pentoxy-3-methoxy-benzamidine,190)N-hydroxy-2-cyclohexylamino-4-5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)-phenoxy]-pentoxy-benzamidine,191)N-hydroxy-4-5-[3-fluoro-4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)-phenoxy]-pentoxy-benzamidine,192)N-hydroxy-2-fluoro-4-5-[3-fluoro-4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)-phenoxy]-pentoxy-benzamidine,193)N-hydroxy-4-3-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)phenoxy]propoxy-benzamidine,194)N-hydroxy-4-4-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)phenoxy]butoxy-benzamidine,195)N-hydroxy-3-5-[4-(5-isopropyl-2-methyl-thiazol-4-yl)-phenoxy]-pentylamino-benzamidine,196)N-hydroxy-4-4-[4-(2-cyclohexyl-5-ethyl-thiazol-4-yl)-phenoxy]-butoxy-benzamidine,197)N-hydroxy-4-[(5-(4-5-ethyl-2-[(2-hydroxyethyl)-methyl-amino]-thiazol-4-yl)phenoxy]propoxy-benzamidine,198)N-hydroxy-4-[5-(4-5-ethyl-2-[(2-hydroxyethyl)-methyl-amino]-thiazol-4-yl)phenoxy]butoxy-benzamidine,199)N-hydroxy-4-[5-(4-5-ethyl-2-[methyl-(pyridin-3-yl-methyl)amino]-thiazol-4-yl)phenoxy]propoxy-benzamidine,200)N-hydroxy-4-[5-(4-5-ethyl-2-[methyl-(pyridin-3-yl-methyl)amino]-thiazol-4-yl)phenoxy]butoxy-benzamidine,201)N-hydroxy-4-4-[4-(5-cyclopentylmethyl-2-isopropyl-thiazol-4-yl)-phenoxymethyl]-benzyloxy-benzamidine,202)N-hydroxy-4-4-[4-(5-butyl-2-isopropyl-thiazol-4-yl)-phenoxymethyl]-benzyloxy-benzamidine,203)N-hydroxy-4-4-[4-(5-cyclopentylmethyl-2-amino-thiazol-4-yl)-phenoxymethyl]-benzyloxy-benzamidine,204)N-hydroxy-4-4-[4-(5-cyclopentylmethyl-2-amino-thiazol-4-yl)-phenoxymethyl]-benzyloxy-2-fluoro-benzamidine,205)N-hydroxy-4-4-[4-(2-methylamino-thiazol-4-yl)-phenoxymethyl]-benzyloxy-benzamidine,206)N-hydroxy-4-6-[4-(5-isopropyl-2-methyl-thiazol-4-yl)-phenoxymethyl]-pyridin-2-yl-methoxy-benzamidine,207)N-hydroxy-2-fluoro-4-5-[4-(5-isopropyl-2-methyl-thiazol-4-yl)-phenoxy]-butoxy-benzamidine,208)N-hydroxy-4-2-[4-(5-isopropyl-2-methyl-thiazol-4-yl)-phenoxymethyl]-benzyloxy-benzamidine,209)N-hydroxy-4-3-[4-(5-isopropyl-2-methyl-thiazol-4-yl)-phenoxymethyl]-benzyloxy-benzamidine,210)N-hydroxy-4-4-[4-(5-cyclopentylmethyl-2-cyclohexyl-thiazol-4-yl)-phenoxymethyl]-benzyloxy-benzamidine,211)N-hydroxy-4-6-[4-(5-isopropyl-2-methyl-thiazol-4-yl)phenoxy]-hexyloxy-benzamidine,212)N-hydroxy-4-5-[2-ethyl-5-hydroxy-4-(2-methyl-thiazol-4-yl)phenoxy]-pentyloxy-benzamidine,and 213)N-hydroxy-4-5-[2-ethyl-4-(2-methyl-thiazol-4-yl)-5-propoxy-phenoxy]-pentyloxy-benzamidine;or pharmaceutically acceptable salts thereof.
 7. A process for producinga compound of the formula 1a or pharmaceutically acceptable saltsthereof which comprises the steps of 1) reacting a compound of theformula 2 with a compound of the formula 3 in the presence of inorganicbase to prepare a compound of the formula 4, 2) reacting a compound ofthe formula 5 with acid chloride of the formula 6 in the presence ofinorganic acid to prepare phenone of the formula 7, and reacting thephenone of the formula 7 with acid to prepare a compound of the formula8, 3) reacting the compound of the formula 4 prepared in step 1) withthe compound of the formula 8 prepared in step 2) in the presence ofinorganic base to prepare benzonitrile derivatives of the formula 9, 4)reacting the compound of the formula 9 prepared in step 3) withbrominating agent to prepare α-brominated compound of the formula 10, 5)reacting α-brominated compound of the formula 10 prepared in step 4)with thioamide compound of the formula 11 to prepare benzonitrilederivatives with thiazole ring of the formula 12, and 6) reacting thecompound of the formula 12 prepared in step 5) with amine compound toprepare benzamidine derivatives of the formula 1a.

wherein R₁ is C₁˜C₆ alkyl; pyridine-substituted C₁˜C₆ alkyl; C₃˜C₆cycloalkyl; benzyl; phenyl; amino; guanidino; pyridinyl; C₁˜C₆alkyl-substituted pyridinyl; or

wherein A is C₁˜C₆ alkyl and n is integer of 2 to 6; and R₂, R₃, R₄, R₅,X₁, X₂ and X₃ are defined in claim
 1. 8. A process for producing acompound of the formula 1b or pharmaceutically acceptable salts thereofwhich comprises the steps of 1) reacting a compound of the formula 2with a compound of the formula 3 in the presence of inorganic base toprepare a compound of the formula 4, 2) reacting a compound of theformula 5 with acid chloride of the formula 6 in the presence ofinorganic acid to prepare phenone of the formula 7, and reacting thephenone of the formula 7 with acid to prepare a compound of the formula8, 3) reacting the compound of the formula 4 prepared in step 1) withthe compound of the formula 8 prepared in step 2) in the presence ofinorganic base to prepare benzonitrile derivatives of the formula 9, 4)reacting the compound of the formula 9 prepared in step 3) withbrominating agent to prepare α-brominated compound of the formula 10, 5)reacting α-brominated compound of the formula 10 prepared in step 4)with thiourea of the formula 13 to prepare benzonitrile derivatives withaminothiazole ring of the formula 14, 6) reacting the compound of theformula 14 prepared in step 5) with halide compound of the formula 15 toprepare benzonitrile derivatives with thiazole ring substituted withprimary amine of the formula 16, and 7) reacting the compound of theformula 16 prepared in step 6) with amine compound to preparedbenzamidine derivatives of the formula 1b.

wherein R₂, R₃, R₄, R₅, R₆, X₁, X₂ and X₃ are defined in claim 1 and nis an integer of 0 to 6, with the proviso that R₆ is not hydrogen
 9. Aprocess for producing a compound of the formula 1c or pharmaceuticallyacceptable salts thereof which comprises the steps of 1) reacting acompound of the formula 2 with a compound of the formula 3 in thepresence of inorganic base to prepare a compound of the formula 4, 2)reacting a compound of the formula 5 with acid chloride of the formula 6in the presence of inorganic acid to prepare phenone of the formula 7,and reacting the phenone of the formula 7 with acid to prepare acompound of the formula 8, 3) reacting the compound of the formula 4prepared in step 1) with the compound of the formula 8 prepared in step2) in the presence of inorganic base to prepare benzonitrile derivativesof the formula 9, 4) reacting the compound of the formula 9 prepared instep 3) with brominating agent to prepare α-brominated compound of theformula 10, 5) reacting α-brominated compound of the formula 10 preparedin step 4) with thiourea of the formula 13 to prepare benzonitrilederivatives with aminothiazole ring of the formula 14, 6) reacting thecompound of the formula 14 prepared in step 5) with halide compound ofthe formula 15 to prepare benzonitrile derivatives with thiazole ringsubstituted with primary amine of the formula 16, 7) reacting thecompound of the formula 16 prepared in step 6) above with a compound ofthe formula 17 to prepare benzonitrile derivatives with thiazole ringsubstituted with secondary amine of the formula 18, and 8) reacting thecompound of the formula 18 prepared in step 7) with amine compound toprepare benzamidine derivatives of the formula 1c.

wherein R₂, R₃, R₄, R₅, R₆, R₇, X₁, X₂ and X₃ are defined in claim 1 andn is integer of 0 to 6, with the proviso that R₆, R7 and both of themare not hydrogen.
 10. A process for producing a compound of the formula1d or pharmaceutically acceptable salts thereof which comprises thesteps of 1) reacting a compound of the formula 2 with a compound of theformula 3 in the presence of inorganic base to prepare a compound of theformula 4, 2) reacting a compound of the formula 5 with acid chloride ofthe formula 6 in the presence of inorganic acid to prepare phenone ofthe formula 7, and reacting the phenone of the formula 7 with acid toprepare a compound of the formula 8, 3) reacting the compound of theformula 4 prepared in step 1) with the compound of the formula 8prepared in step 2) in the presence of inorganic base to preparebenzonitrile derivatives of the formula 9, 4) reacting the compound ofthe formula 9 prepared in step 3) with brominating agent to prepareα-brominated compound of the formula 10, 5) reacting α-brominatedcompound of the formula 10 prepared in step 4) with thiourea of theformula 13 to prepare benzonitrile derivatives with aminothiazole ringof the formula 14, 6) reacting the compound of the formula 14 preparedin step 5) with the compound of which both terminals are halogenated ofthe formula 19 to prepare benzonitrile derivatives with thiazole ringsubstituted with hetero atom ring of the formula 20, and 7) reacting thecompound of the formula 20 prepared in step 6) with amine compound toprepare benzamidine derivatives of the Formula 1d.

wherein R₂, R₃, R₄, R₅, X₁, X₂ and X₃ are defined in claim 1 and n isinteger of 0 to
 6. 11. The process according to claim 7 wherein thecompound of the formula 11 is selected from the group consisting ofthioacetamide, thiopropionamide, thioisobutramide,trimethylthioacetamide, thiohexanoylamide, cyclohexanecarbothioic acideamide, and piperidin-4-carbothioic acid amide.
 12. The process accordingto claim 8 or 9 wherein the halide compound of the formula 15 and 17 isselected from the group consisting of iodomethane, iodoethane, propylbromide, 2-chloroethyl methyl ether, 2-chloroethylmorpholine,3-bromomethylpyridine, 2-bromoethanol, niconoyl chloride, benzylbromide, nicotinoyl chloride, ethanesulfonyl chloride and isoniconoylchloride.
 13. The process according to claim 10, wherein the compound ofwhich both terminals are halogenated of the formula 19 ismechloethylamine, dibromoethylether or dibromopentane.
 14. The processaccording to any one of claims 7 to 10, wherein, in the conversion ofbenzonitrile into benzamidine, where R₅ is OH, hydroxylaminehydrochloride is used as amine; and the amine is reacted in the presenceof a base, wherein the base is organic bases selected fromtriethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, DBU,diethylmethylamine (Et₂NMe), N-methylmorpholine, N-methylpiperidine,pyridine and 2,6-dimethylpyridine, or inorganic bases selected frompotassium carbonate, potassium bicarbonate, sodium hydroxide, potassiumhydroxide, sodium amide, sodium hydride, sodium methoxide and sodiumethoxide, at a temperature of 60 to 80° C. for 1 to 9 hours in methanol,ethanol, acetonitrile or its mixture with water.
 15. The processaccording to any one of claims 7 to 10 wherein, in the conversion ofbenzonitrile into benzamidine, where R₅ is H, methoxy imine preparedfrom hydrochloride methanol solution at a temperature of 10 to 30° C.for 24 to 48 hours, is reacted with ammonia ethanol solution at atemperature of 45 to 60° C. for 24 to 50 hours.
 16. A pharmaceuticalcomposition for the prevention and treatment of osteoporosis comprisingthe compound of the formula 1 according to claim 1 or pharmaceuticalacceptable salts thereof.
 17. A pharmaceutical composition for theprevention and treatment of bone fracture comprising the compound of theformula 1 according to claim 1 or pharmaceutical acceptable saltsthereof.
 18. A pharmaceutical composition for the prevention andtreatment of allergic inflammatory diseases comprising the compound ofthe formula 1 according to claim 1 or pharmaceutical acceptable saltsthereof.
 19. The pharmaceutical composition according to claim 18wherein allergic inflammatory disease is asthma.